The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3.
ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.101T>C (p.Met34Thr)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_004004.6(GJB2):c.101T>C (p.Met34Thr)
Variation ID: 17000 Accession: VCV000017000.104
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q12.11 13: 20189481 (GRCh38) [ NCBI UCSC ] 13: 20763620 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 3, 2013 Oct 20, 2024 Jun 24, 2019 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004004.6:c.101T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met34Thr missense NC_000013.11:g.20189481A>G NC_000013.10:g.20763620A>G NG_008358.1:g.8495T>C LRG_1350:g.8495T>C LRG_1350t1:c.101T>C LRG_1350p1:p.Met34Thr P29033:p.Met34Thr - Protein change
- M34T
- Other names
-
rs35887622
NM_004004.5(GJB2):c.101T>C
- Canonical SPDI
- NC_000013.11:20189480:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00599 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00578
1000 Genomes Project 0.00599
Trans-Omics for Precision Medicine (TOPMed) 0.00745
Exome Aggregation Consortium (ExAC) 0.00850
The Genome Aggregation Database (gnomAD), exomes 0.00868
The Genome Aggregation Database (gnomAD) 0.00966
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
570 | 637 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (18) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000018523.84 | |
| Pathogenic/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Apr 8, 2024 | RCV000080364.75 | |
| Pathogenic (2) |
reviewed by expert panel
|
Jun 24, 2019 | RCV000211758.11 | |
| no classifications from unflagged records (2) |
no classifications from unflagged records
|
Aug 9, 2024 | RCV000487479.20 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Apr 1, 2023 | RCV000678866.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2024 | RCV000844701.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2021 | RCV001027827.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 25, 2023 | RCV001266565.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004397.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 5, 2016 | RCV001270137.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 12, 2021 | RCV001375142.11 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 21, 2022 | RCV002251910.9 |
|
GJB2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 20, 2024 | RCV004724749.1 |
| not provided (1) |
no classification provided
|
- | RCV004700251.1 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 24, 2019)
|
reviewed by expert panel
Method: curation
|
Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hearing Loss Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000927015.1 First in ClinVar: Jul 22, 2019 Last updated: Jul 22, 2019 |
Comment:
The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for … (more)
The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. (less)
|
|
|
Likely pathogenic
(Mar 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538034.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.101T>C (p.Met34Thr) missense variant in the GJB2gene has been previously reported in numerous individuals with autosomal recessive Nonsyndromic hearing loss and has been shown … (more)
The c.101T>C (p.Met34Thr) missense variant in the GJB2gene has been previously reported in numerous individuals with autosomal recessive Nonsyndromic hearing loss and has been shown to segregate with disease (Houseman et al., 2001; Bicego et al., 2006; Löppönen et al., 2012).This variant has been observed in trans with the well-characterized GJB2 c.35delG variant (Houseman et al., 2001; Bicego et al., 2006; Pollack et al., 2007). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Martin et al., 1999; D'Andrea et al., 2002; Bicego et al., 2006). The c.101T>C variant has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC ); however, this variant has been observed as homozygous in 13 individuals in ExAC. Multiple lines of computational evidence predict a deleterious effect. In addition, multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.101T>C (p.Met34Thr) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss. (less)
|
|
|
Pathogenic
(Feb 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193154.2
First in ClinVar: Nov 23, 2014 Last updated: Nov 10, 2017 |
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138911.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Autosomal recessive nonsyndromic hearing loss 1B
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163369.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Pathogenic
(Feb 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698223.4
First in ClinVar: Feb 15, 2018 Last updated: Mar 07, 2020 |
Comment:
Variant summary: GJB2 c.101T>C (p.Met34Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of … (more)
Variant summary: GJB2 c.101T>C (p.Met34Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 1604678 control chromosomes including 26 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. c.101T>C has been well reported in the literature in studies of individuals affected with hearing loss phenotypes (example, Houseman_2001 through Shen_2019). These data indicate that the variant is likely to be associated with disease. Many publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity measured as Cx26 hemichannel activated conductance following depolarization (example, Palmada_2006). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments although a majority of these assessments support a pathogenic outcome. Furthermore, the ClinGen Hearing Loss Expert Panel has classified it as Pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance (Shen_2019). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
unknown
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244778.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
The NM_004004.5(GJB2):c.101T>C missense variant was identified in exon 2of GJB2. This substitution is predicted to create a moderate amino acid change from a methionine to … (more)
The NM_004004.5(GJB2):c.101T>C missense variant was identified in exon 2of GJB2. This substitution is predicted to create a moderate amino acid change from a methionine to a threonine at amino acid position 34, NP_003995.2(GJB2):p.(Met34Thr). The methionine at this position has high conservation (100 vertebrates, UCSC). In silico software predictions of the pathogenicity of this variant are conflicting. It is situated in a transmembrane helix of theGJB2 protein. This variant has been observed in a population database at a frequency of 0.008% with 26 homozygotes observed (ExAC, GnomAD). However, this variant has been reported as a pathogenic variant in homozygous or compound heterozygous state, andbeen shown to segregate with disease in multiple families with hearing loss (ClinVar, Deafness variantion database, The connexin-deafness homepage). Based on current information and in association with the NM_004004.5(GJB2):c.550C>T variant, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 4
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Deafness, autosomal recessive 1A
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251549.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The GJB2 c.101T>C (p.M34T) variant has been reported as a mild (hypomorphic) variant that leads to mild to moderate hearing loss when found in the … (more)
The GJB2 c.101T>C (p.M34T) variant has been reported as a mild (hypomorphic) variant that leads to mild to moderate hearing loss when found in the homozygous state or in trans with a more severe pathogenic GJB2 variant (PMID: 22668073; 11134236; 20708129; 17935238). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194149.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_004004.5(GJB2):c.101T>C(M34T) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with bilateral mild to moderate … (more)
NM_004004.5(GJB2):c.101T>C(M34T) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 10556284, 16849369, 15033936, 9716127, 23826813 and 16380907. Classification of NM_004004.5(GJB2):c.101T>C(M34T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Aug 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
INGEBI, INGEBI / CONICET
Accession: SCV001434021.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3, PP3.
Number of individuals with the variant: 16
Clinical Features:
Poslingual profound hearing loss (present) , Postlingual moderate hearing loss (present)
Family history: yes
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
|
|
|
Pathogenic
(Aug 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hearing loss, non-syndromic
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449019.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 5
Sex: male
|
|
|
Pathogenic
(Sep 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450277.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Jun 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
paternal
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV001745838.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss.
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Feb 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523022.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PP3
Clinical Features:
Neurodevelopmental abnormality (present) , Colpocephaly (present) , Autistic behavior (present) , Abnormal corpus callosum morphology (present)
|
|
|
Pathogenic
(Jul 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579816.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PP1_STR, PM3, PP3
|
Number of individuals with the variant: 3
Sex: female
|
|
|
Pathogenic
(Dec 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Palmoplantar keratoderma-deafness syndrome
Autosomal recessive nonsyndromic hearing loss 1A Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss Knuckle pads, deafness AND leukonychia syndrome Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Mutilating keratoderma
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190447.2
First in ClinVar: Mar 26, 2020 Last updated: May 06, 2023 |
Comment:
GJB2 NM_004004.5 exon 2 p.Met34Thr (c.101T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with … (more)
GJB2 NM_004004.5 exon 2 p.Met34Thr (c.101T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with mild to severe nonsyndromic hearing loss, as well as in both affected and unaffected relatives, suggesting that this variant may have reduced penetrance or may act as a modifier of disease (Kelsell 1997 PMID:9139825, Houseman 2001 PMID:11134236, D'Andrea 2002 PMID:12176036, Feldmann 2004 PMID:14694360, Bicego 2006 PMID:16849369, Pollak 2007 PMID:17935238, Lopponen 2012 PMID:22668073, Lameiras 2015 PMID:26117665, Mikstiene 2016 PMID:26896187). This variant is also present in 2% (510/25108) of Finnish alleles in the Genome Aggregation Database, including 9 homozygotes (https://gnomad.broadinstitute.org/variant/13-20763620-A-G), which may indicate that it is a common variant or a risk allele in this population. This variant is also present in ClinVar, with classifications ranging from pathogenic to benign (Variation ID:17000). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will lead to abnormal channel function (Martin 1999 PMID:10556284, D'Andrea 2002 PMID:12176036, Bicego 2006 PMID:16849369). However, at least one study did not demonstrate this (Oshima 2003 PMID:12384501). These studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. (less)
|
|
|
Pathogenic
(Oct 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospital and Clinics
Accession: SCV000264324.2
First in ClinVar: Feb 26, 2016 Last updated: May 13, 2023 |
Comment:
This variant has required extensive investigation to determine its clinical significance. It does have high minor allele frequency in several populations (including 2.2% in the … (more)
This variant has required extensive investigation to determine its clinical significance. It does have high minor allele frequency in several populations (including 2.2% in the European Finnish population within ExAC). Conversely, there is significant literature evidence that this variant is pathogenic with a variable hearing phenotype. (less)
Observation 1:
Clinical Features:
Hearing impairment (present)
Age: 2-9 years
Sex: mixed
Ethnicity/Population group: Caucasian
Comment on evidence:
Diagnosed individuals with M34T in 1119 clinical patients
Method: Targeted genomic enrichment and massively parallel sequencing to target non-syndromic hearing loss and non-syndromic hearing loss mimics. More explicit methods can be found in PMID: 23804846
Observation 2:
Clinical Features:
Hearing impairment (present)
Age: 1-16 years
Sex: mixed
Ethnicity/Population group: Unknown
Comment on evidence:
Diagnosed individuals with M34T in 1119 clinical patients
Method: Targeted genomic enrichment and massively parallel sequencing to target non-syndromic hearing loss and non-syndromic hearing loss mimics. More explicit methods can be found in PMID: 23804846
|
|
|
Pathogenic
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935285.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
|
|
|
Pathogenic
(Aug 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225746.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3
Number of individuals with the variant: 6
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Pathogenic
(Dec 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000841697.4
First in ClinVar: Feb 15, 2018 Last updated: Jan 26, 2024 |
Comment:
This variant is one of the most common variants associated with autosomal recessive nonsyndromic hearing loss and is reported to have milder disease presentation and … (more)
This variant is one of the most common variants associated with autosomal recessive nonsyndromic hearing loss and is reported to have milder disease presentation and reduced penetrance in some families (PMID: 11134236, 16380907, 22668073). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in reduced cell to cell transfer of small molecules (PMID: 12176036, 12189493, 16300957, 16849369, 27884957). (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001105249.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the GJB2 protein (p.Met34Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the GJB2 protein (p.Met34Thr). This variant is present in population databases (rs35887622, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 16077952, 22668073, 26117665; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported to show reduced penetrance (PMID: 31160754). ClinVar contains an entry for this variant (Variation ID: 17000). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603813.10
First in ClinVar: Jan 26, 2017 Last updated: Feb 20, 2024 |
Comment:
The GJB2 pathogenic mild c.101T>C; p.Met34Thr variant (rs35887622) is reported in ClinVar (Variation ID: 17000), and observed in the Genome Aggregation Database with an overall … (more)
The GJB2 pathogenic mild c.101T>C; p.Met34Thr variant (rs35887622) is reported in ClinVar (Variation ID: 17000), and observed in the Genome Aggregation Database with an overall allele frequency of 0.9% (2538/282130 alleles, including 28 homozygotes). This variant has been previously classified as benign based on population frequency data (Shearer 2014), and has been referred to as a variant with reduced penetrance (Feldmann 2004, Griffith 2000, Pollak 2007, Tang 2006). However, homozygosity for this variant has also been reported to co-segregate with mild to high frequency deafness (Hall 2012, Houseman 2001). Additionally, this variant has been to shown to have a variable phenotype within the same family (Lameiras 2015). Taken together, we consider this variant to be mildly pathogenic. References: Feldmann D et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004 Apr;12(4):279-84. PMID: 14694360. Griffith AJ et al. Autosomal recessive non-syndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000 Sep;67(3):745-9. PMID: 10903123. Hall A et al. Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study. BMJ Open. 2012 Jul 31;2(4). PMID: 22855627. Houseman MJ et al. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet. 2001 Jan;38(1):20-5. PMID: 11134236. Lameiras AR et al. The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. Int J Pediatr Otorhinolaryngol. 2015 Aug;79(8):1316-9. PMID: 26117665. Pollak et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007; 143A(21): 2534-2543. PMID: 17935238. Shearer AE et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53. PMID: 25262649. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22): 2401-2415. PMID: 17041943. (less)
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Pathogenic
(Apr 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061472.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Met34Thr variant in GJB2 is well-established as a pathogenic variant. This variant, in homozygosity or in combination with another GJB2 variant, is commonly associated … (more)
The p.Met34Thr variant in GJB2 is well-established as a pathogenic variant. This variant, in homozygosity or in combination with another GJB2 variant, is commonly associated with mild to moderate hearing loss (Pollak 2007 PMID: 17935238, Snoeckx 2005 PMID: 16380907, Shen 2019 PMID: 31160754) and in rare cases, p.Met34Thr may even be associated with normal hearing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM3_VeryStrong. (less)
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Pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444741.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.101T>C (p.M34T) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from a T to C substitution … (more)
The c.101T>C (p.M34T) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the methionine (M) at amino acid position 34 to be replaced by a threonine (T). _x000D_ _x000D_ for autosomal recessive GJB2-related non-syndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related non-syndromic hearing loss and autosomal dominant GJB2-related non-syndromic hearing loss with ectodermal involvement is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.900% (2538/282130) total alleles studied. The highest observed frequency was 2.031% (510/25108) of European (Finnish) alleles. This alteration has been found to be statistically enriched in patients with non-syndromic sensorineural hearing loss and has been reported to be homozygous or compound heterozygous with a second GJB2 disease-causing allele in multiple affected individuals (Shen, 2019). In addition, this alteration has been shown to segregate with disease (Shen, 2019; Griffith, 2000). Both incomplete penetrance and and variable expressivity of hearing loss has been reported in families and individuals with this alteration and a second-disease causing allele. This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051789.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198029.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Apr 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321726.8
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Common GJB2 variant among individuals of European background, with a carrier frequency of about 1% in Europeans (PMID: 31160754; gnomAD); Case control studies suggest this … (more)
Common GJB2 variant among individuals of European background, with a carrier frequency of about 1% in Europeans (PMID: 31160754; gnomAD); Case control studies suggest this variant is associated with hearing loss; homozygous and compound heterozygous genotypes are statistically enriched in individuals with autosomal recessive nonsyndromic hearing loss compared to the general population (PMID: 31160754); Published functional studies demonstrate a dominant-negative effect leading to impaired intercellular coupling (PMID: 9139825, 10556284, 16849369); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927015.1; ClinVar; PMID: 31160754); This variant is associated with the following publications: (PMID: 21465647, 16300957, 12176036, 25262649, 15070423, 14694360, 11216656, 30094485, 30311386, 35054374, 34761457, 34697415, 22668073, 25214170, 10757647, 22975760, 22995991, 10556284, 12189493, 12384501, 20668687, 9716127, 26117665, 26896187, 11134236, 27153395, 17935238, 22567861, 10888284, 17426645, 9600457, 25388846, 22855627, 9139825, 10830906, 30609409, 29773520, 31163360, 30344259, 31827275, 31980526, 30872718, 31160754, 10903123, 23826813, 34426522, 33096615, 16077952, 33297549, 33105617, 34515852, 37838930, 36675424, 37108562, 36515421, 36048236, 16849369, 16380907, 34599368, 20083784) (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950000.4
First in ClinVar: Oct 02, 2021 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3_MOD,PM3_VSTR,PM5_STR,PP1_VSTR,PP3
Clinical Features:
Hearing impairment (present)
Sex: female
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500565.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Comment:
GJB2: PM3:Very Strong, PM5, PM2:Supporting
Number of individuals with the variant: 21
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Likely pathogenic
(Jun 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000383043.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
Across a selection of literature, the GJB2 c.101T>C (p.Met34Thr) missense variant has been identified in at least 119 patients with an autosomal recessive form of … (more)
Across a selection of literature, the GJB2 c.101T>C (p.Met34Thr) missense variant has been identified in at least 119 patients with an autosomal recessive form of nonsyndromic hearing loss. The variant was found in a homozygous state in 35 patients, in a compound heterozygous state in 66 patients (at least 59 of whom had a pathogenic deletion), and in a heterozygous state in 18 patients (Houseman et al, 2001; Feldmann et al. 2004; Snoeckx et al. 2005; Tang et al. 2006; Pollak et al. 2007; Löppönen et al. 2012; Dória et al. 2015; Mikstiene et al. 2016). This variant is generally associated with mild to moderate nonsyndromic hearing loss, and segregation was observed in a three-generation family (Löppönen et al. 2012). The p.Met34Thr variant was detected in 66 of 5380 control chromosomes mainly in a heterozygous state, and also in family members with normal audiograms, including in two with the variant in a homozygous state, in five with the variant in a compound heterozygous state, and in 23 with the variant in a heterozygous state (Feldmann et al. 2004; Löppönen et al. 2012). This conflicting evidence may be due to reduced penetrance, estimated at 10% in one study (Pollak et al. 2007), presence of other modifying factors (Houseman et al, 2001; Bicego et al. 2006), or due to an age-dependent effect (Pollak et al. 2007). Dória et al. (2015) suggest this variant may be a risk factor for nonsyndromic hearing loss. Functional studies suggest this variant affects intercellular channels based on dye transfer assays in transiently transfected HeLa cells (D'Andrea et al. 2002; Bicego et al. 2006), although at least one study did not observe this (Oshima et al. 2003). In addition, electrical conductance was decreased to 11% of wildtype in the presence of the p.Met34Thr variant (Bicego et al. 2006). The p.Met34Thr variant is reported at a frequency of 0.03535 in the Finnish population of the 1000 Genomes Project. Based on the evidence, the p.Met34Thr variant is classified as likely pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700273.2
First in ClinVar: May 07, 2017 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 54
Sex: mixed
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448122.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cerebellar ataxia (present) , Hearing impairment (present)
Sex: female
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Pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001572151.2
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment:
PS1_Very strong, PS4_Strong, PM5_Moderate
Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
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Pathogenic
(Jun 10, 2015)
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no assertion criteria provided
Method: research
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Deafness, autosomal recessive 1A
Affected status: no
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238468.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The GJB2 variant (c.101T>C; p.Met34Thr) was identified in several individuals with hearing loss and segregated in families with mild non-syndromic hearing loss (Lopponen et. al … (more)
The GJB2 variant (c.101T>C; p.Met34Thr) was identified in several individuals with hearing loss and segregated in families with mild non-syndromic hearing loss (Lopponen et. al 2012; PMID 22668073) with functional studies supporting pathogenicity (Kelsell et al. 1997, PMID 9139825; Martin et al. 1999, PMID 10556284, Lopponen et. al 2012; PMID 22668073 and Shearer et al. 2014, PMID 2562649). However, this variant is quite prevalent in control databases (1049 alleles out of 122876 and 13 homozygotes in ExAC) and could be associated with reduced penetrance. Other clinical laboratories have classified this variant as pathogenic (SCV000061472 and SCV000112260) and variant of uncertain significance (SCV000193154). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548892.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GJB2 p.M34T variant was identified in the literature in multiple individuals with by hearing loss, and is reported as a pathogenic variant for autosomal … (more)
The GJB2 p.M34T variant was identified in the literature in multiple individuals with by hearing loss, and is reported as a pathogenic variant for autosomal recessive nonsyndromic hearing loss with variable expressitivity and incomplete penetrance by the ClinGen Hearing Loss Expert Panel (Coco_2013_PMID_24611097; Doria_2015; Shen_2019_PMID_31160754). The variant was also found to segregate with disease in two Portuguese compound heterozygote siblings, although the siblings exhibited different phenotypes as one exhibited profound hearing loss, while the other sibling only had moderate hearing loss (Lameiras_2015_PMID_26117665). The variant was identified in dbSNP (ID: rs35887622) and ClinVar (classified as pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel for Nonsyndromic hearing loss and deafness and 11 laboratories, as likely pathogenic by Knight Diagnostic Laboratories, as uncertain significance by Johns Hopkins and Division of Human Genetics, Children's Hospital of Philadelphia, as likely benign by Prevention Genetics, and as benign by Invitae). The variant was identified in control databases in 2538 of 282130 chromosomes (28 homozygous) at a frequency of 0.008996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 510 of 25108 chromosomes (freq: 0.02031), European (non-Finnish) in 1655 of 128490 chromosomes (freq: 0.01288), Other in 65 of 7214 chromosomes (freq: 0.00901), Ashkenazi Jewish in 82 of 10358 chromosomes (freq: 0.007917), Latino in 163 of 35426 chromosomes (freq: 0.004601) and African in 63 of 24968 chromosomes (freq: 0.002523), but was not observed in the East Asian or South Asian populations. The p.M34 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies suggest that this variant alters gap junction function in Xenopus oocytes and mammalian cells (White_1998; Skerrett_2004_PMID_ 15033936; Martin_1999_PMID_ 10556284; Thonnissen_2002_PMID_ 12189493; Bicego_2006_PMID_ 16849369; Zonta_2014_PMID_ 24624091; D’Andrea_2002_PMID_ 12176036). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Sep 20, 2024)
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no assertion criteria provided
Method: clinical testing
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GJB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000309913.4
First in ClinVar: Oct 02, 2016 Last updated: Oct 08, 2024 |
Comment:
The GJB2 c.101T>C variant is predicted to result in the amino acid substitution p.Met34Thr. This variant has been reported to be causative for mild to … (more)
The GJB2 c.101T>C variant is predicted to result in the amino acid substitution p.Met34Thr. This variant has been reported to be causative for mild to moderate autosomal recessive hearing loss with reduced penetrance (Wu et al. 2002. PubMed ID: 12172394; Bicego et al. 2006. PubMed ID: 16849369; Pollak et al. 2007. PubMed ID: 17935238; Mikstiene et al. 2016. PubMed ID: 26896187; Lameiras et al. 2015. PubMed ID: 26117665). Three other amino acid substitutions at the same position (Met34Val, Met34Leu and Met34Arg) have also been reported to be causative for hearing loss. The ClinGen Hearing Loss expert panel has classified this variant as pathogenic for autosomal recessive nonsyndromic hearing loss, noting hearing loss is typically mild with incomplete penetrance (https://www.ncbi.nlm.nih.gov/clinvar/variation/17000/; Shen et al. 2019. PubMed ID: 31160754). This variant is interpreted as pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal dominant nonsyndromic hearing loss 3A
Autosomal recessive nonsyndromic hearing loss 1A
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV001423221.2
First in ClinVar: Jul 19, 2020 Last updated: Sep 16, 2024 |
Comment:
Variant interpretted as Pathogenic and reported on 02-12-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing … (more)
Variant interpretted as Pathogenic and reported on 02-12-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Overgrowth (present) , Obesity (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test … (more)
Overgrowth (present) , Obesity (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Elevated circulating growth hormone concentration (present) , Tall stature (present) , Type 2 diabetes mellitus (present) , Diabetes mellitus type 1 (present) , Delayed puberty (present) , Diabetes insipidus (present) , Precocious puberty (present) , Hypogonadism (present) , Adrenal hyperplasia (present) , Goiter (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Sensorineural hearing loss disorder (present) , Tinnitus (present) , Vertigo (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Memory impairment (present) , Movement disorder (present) , Autistic behavior (present) , Anxiety (present) , Cafe au lait spots, multiple (present) , Hyperpigmentation of the skin (present) , Abnormal curvature of the vertebral column (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Cardiomyopathy (present) , Abnormality of the cardiovascular system (present) , Abnormal cardiovascular system morphology (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Asthma (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) , Abnormality of the liver (present) , Gastrointestinal dysmotility (present) , Abnormal intestine morphology (present) , Abnormality of the bladder (present) , Abnormal renal morphology (present) , Abnormality of urine homeostasis (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Rheumatoid arthritis (present) , Bleeding with minor or no trauma (present) , Abnormal erythrocyte morphology (present) , Abnormal leukocyte morphology (present) , Abnormality of blood and blood-forming tissues (present) (less)
Age: 40-49 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-02-12
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041038.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Uncertain significance
(May 09, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
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Deafness, autosomal recessive 1A
Affected status: no, yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599729.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 39
Observation 2:
Number of individuals with the variant: 11
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Uncertain significance
(Dec 29, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
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Hearing loss
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805059.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(Mar 07, 2021)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Other
Notes: Variant is not associated with dominant hearing loss, only recessive.
(less)
Notes: Variant is not
(...more)
Source: ClinGen
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835751.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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not provided
(-)
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Flagged submission
flagged submission
Method: literature only
Reason: Other
Notes: The variant is not associated to dominant hearing loss, only recessive.
(less)
Notes: The variant is not
(...more)
Source: ClinGen
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000574679.2
First in ClinVar: May 07, 2017 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The c.101T>C (p.Met34Thr) missense variant in the GJB2gene has been previously reported in numerous individuals with autosomal recessive Nonsyndromic hearing loss and has been shown to segregate with disease (Houseman et al., 2001; Bicego et al., 2006; Löppönen et al., 2012).This variant has been observed in trans with the well-characterized GJB2 c.35delG variant (Houseman et al., 2001; Bicego et al., 2006; Pollack et al., 2007). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Martin et al., 1999; D'Andrea et al., 2002; Bicego et al., 2006). The c.101T>C variant has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC ); however, this variant has been observed as homozygous in 13 individuals in ExAC. Multiple lines of computational evidence predict a deleterious effect. In addition, multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.101T>C (p.Met34Thr) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss.
Comment:
Variant summary: GJB2 c.101T>C (p.Met34Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 1604678 control chromosomes including 26 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. c.101T>C has been well reported in the literature in studies of individuals affected with hearing loss phenotypes (example, Houseman_2001 through Shen_2019). These data indicate that the variant is likely to be associated with disease. Many publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity measured as Cx26 hemichannel activated conductance following depolarization (example, Palmada_2006). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments although a majority of these assessments support a pathogenic outcome. Furthermore, the ClinGen Hearing Loss Expert Panel has classified it as Pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance (Shen_2019). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The NM_004004.5(GJB2):c.101T>C missense variant was identified in exon 2of GJB2. This substitution is predicted to create a moderate amino acid change from a methionine to a threonine at amino acid position 34, NP_003995.2(GJB2):p.(Met34Thr). The methionine at this position has high conservation (100 vertebrates, UCSC). In silico software predictions of the pathogenicity of this variant are conflicting. It is situated in a transmembrane helix of theGJB2 protein. This variant has been observed in a population database at a frequency of 0.008% with 26 homozygotes observed (ExAC, GnomAD). However, this variant has been reported as a pathogenic variant in homozygous or compound heterozygous state, andbeen shown to segregate with disease in multiple families with hearing loss (ClinVar, Deafness variantion database, The connexin-deafness homepage). Based on current information and in association with the NM_004004.5(GJB2):c.550C>T variant, this variant has been classified as PATHOGENIC.
Comment:
The GJB2 c.101T>C (p.M34T) variant has been reported as a mild (hypomorphic) variant that leads to mild to moderate hearing loss when found in the homozygous state or in trans with a more severe pathogenic GJB2 variant (PMID: 22668073; 11134236; 20708129; 17935238).
Comment:
NM_004004.5(GJB2):c.101T>C(M34T) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 10556284, 16849369, 15033936, 9716127, 23826813 and 16380907. Classification of NM_004004.5(GJB2):c.101T>C(M34T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3, PP3.
Comment:
This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss.
Comment:
ACMG classification criteria: PS3, PS4, PM2, PP3
Comment:
GJB2 NM_004004.5 exon 2 p.Met34Thr (c.101T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with mild to severe nonsyndromic hearing loss, as well as in both affected and unaffected relatives, suggesting that this variant may have reduced penetrance or may act as a modifier of disease (Kelsell 1997 PMID:9139825, Houseman 2001 PMID:11134236, D'Andrea 2002 PMID:12176036, Feldmann 2004 PMID:14694360, Bicego 2006 PMID:16849369, Pollak 2007 PMID:17935238, Lopponen 2012 PMID:22668073, Lameiras 2015 PMID:26117665, Mikstiene 2016 PMID:26896187). This variant is also present in 2% (510/25108) of Finnish alleles in the Genome Aggregation Database, including 9 homozygotes (https://gnomad.broadinstitute.org/variant/13-20763620-A-G), which may indicate that it is a common variant or a risk allele in this population. This variant is also present in ClinVar, with classifications ranging from pathogenic to benign (Variation ID:17000). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will lead to abnormal channel function (Martin 1999 PMID:10556284, D'Andrea 2002 PMID:12176036, Bicego 2006 PMID:16849369). However, at least one study did not demonstrate this (Oshima 2003 PMID:12384501). These studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.
Comment:
This variant has required extensive investigation to determine its clinical significance. It does have high minor allele frequency in several populations (including 2.2% in the European Finnish population within ExAC). Conversely, there is significant literature evidence that this variant is pathogenic with a variable hearing phenotype.
Comment:
PP3
Comment:
This variant is one of the most common variants associated with autosomal recessive nonsyndromic hearing loss and is reported to have milder disease presentation and reduced penetrance in some families (PMID: 11134236, 16380907, 22668073). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in reduced cell to cell transfer of small molecules (PMID: 12176036, 12189493, 16300957, 16849369, 27884957).
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the GJB2 protein (p.Met34Thr). This variant is present in population databases (rs35887622, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 16077952, 22668073, 26117665; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported to show reduced penetrance (PMID: 31160754). ClinVar contains an entry for this variant (Variation ID: 17000). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The GJB2 pathogenic mild c.101T>C; p.Met34Thr variant (rs35887622) is reported in ClinVar (Variation ID: 17000), and observed in the Genome Aggregation Database with an overall allele frequency of 0.9% (2538/282130 alleles, including 28 homozygotes). This variant has been previously classified as benign based on population frequency data (Shearer 2014), and has been referred to as a variant with reduced penetrance (Feldmann 2004, Griffith 2000, Pollak 2007, Tang 2006). However, homozygosity for this variant has also been reported to co-segregate with mild to high frequency deafness (Hall 2012, Houseman 2001). Additionally, this variant has been to shown to have a variable phenotype within the same family (Lameiras 2015). Taken together, we consider this variant to be mildly pathogenic. References: Feldmann D et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004 Apr;12(4):279-84. PMID: 14694360. Griffith AJ et al. Autosomal recessive non-syndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000 Sep;67(3):745-9. PMID: 10903123. Hall A et al. Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study. BMJ Open. 2012 Jul 31;2(4). PMID: 22855627. Houseman MJ et al. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet. 2001 Jan;38(1):20-5. PMID: 11134236. Lameiras AR et al. The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. Int J Pediatr Otorhinolaryngol. 2015 Aug;79(8):1316-9. PMID: 26117665. Pollak et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007; 143A(21): 2534-2543. PMID: 17935238. Shearer AE et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53. PMID: 25262649. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22): 2401-2415. PMID: 17041943.
Comment:
The p.Met34Thr variant in GJB2 is well-established as a pathogenic variant. This variant, in homozygosity or in combination with another GJB2 variant, is commonly associated with mild to moderate hearing loss (Pollak 2007 PMID: 17935238, Snoeckx 2005 PMID: 16380907, Shen 2019 PMID: 31160754) and in rare cases, p.Met34Thr may even be associated with normal hearing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM3_VeryStrong.
Comment:
The c.101T>C (p.M34T) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the methionine (M) at amino acid position 34 to be replaced by a threonine (T). _x000D_ _x000D_ for autosomal recessive GJB2-related non-syndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related non-syndromic hearing loss and autosomal dominant GJB2-related non-syndromic hearing loss with ectodermal involvement is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.900% (2538/282130) total alleles studied. The highest observed frequency was 2.031% (510/25108) of European (Finnish) alleles. This alteration has been found to be statistically enriched in patients with non-syndromic sensorineural hearing loss and has been reported to be homozygous or compound heterozygous with a second GJB2 disease-causing allele in multiple affected individuals (Shen, 2019). In addition, this alteration has been shown to segregate with disease (Shen, 2019; Griffith, 2000). Both incomplete penetrance and and variable expressivity of hearing loss has been reported in families and individuals with this alteration and a second-disease causing allele. This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Common GJB2 variant among individuals of European background, with a carrier frequency of about 1% in Europeans (PMID: 31160754; gnomAD); Case control studies suggest this variant is associated with hearing loss; homozygous and compound heterozygous genotypes are statistically enriched in individuals with autosomal recessive nonsyndromic hearing loss compared to the general population (PMID: 31160754); Published functional studies demonstrate a dominant-negative effect leading to impaired intercellular coupling (PMID: 9139825, 10556284, 16849369); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927015.1; ClinVar; PMID: 31160754); This variant is associated with the following publications: (PMID: 21465647, 16300957, 12176036, 25262649, 15070423, 14694360, 11216656, 30094485, 30311386, 35054374, 34761457, 34697415, 22668073, 25214170, 10757647, 22975760, 22995991, 10556284, 12189493, 12384501, 20668687, 9716127, 26117665, 26896187, 11134236, 27153395, 17935238, 22567861, 10888284, 17426645, 9600457, 25388846, 22855627, 9139825, 10830906, 30609409, 29773520, 31163360, 30344259, 31827275, 31980526, 30872718, 31160754, 10903123, 23826813, 34426522, 33096615, 16077952, 33297549, 33105617, 34515852, 37838930, 36675424, 37108562, 36515421, 36048236, 16849369, 16380907, 34599368, 20083784)
Comment:
Criteria applied: PS3_MOD,PM3_VSTR,PM5_STR,PP1_VSTR,PP3
Comment:
GJB2: PM3:Very Strong, PM5, PM2:Supporting
Comment:
Across a selection of literature, the GJB2 c.101T>C (p.Met34Thr) missense variant has been identified in at least 119 patients with an autosomal recessive form of nonsyndromic hearing loss. The variant was found in a homozygous state in 35 patients, in a compound heterozygous state in 66 patients (at least 59 of whom had a pathogenic deletion), and in a heterozygous state in 18 patients (Houseman et al, 2001; Feldmann et al. 2004; Snoeckx et al. 2005; Tang et al. 2006; Pollak et al. 2007; Löppönen et al. 2012; Dória et al. 2015; Mikstiene et al. 2016). This variant is generally associated with mild to moderate nonsyndromic hearing loss, and segregation was observed in a three-generation family (Löppönen et al. 2012). The p.Met34Thr variant was detected in 66 of 5380 control chromosomes mainly in a heterozygous state, and also in family members with normal audiograms, including in two with the variant in a homozygous state, in five with the variant in a compound heterozygous state, and in 23 with the variant in a heterozygous state (Feldmann et al. 2004; Löppönen et al. 2012). This conflicting evidence may be due to reduced penetrance, estimated at 10% in one study (Pollak et al. 2007), presence of other modifying factors (Houseman et al, 2001; Bicego et al. 2006), or due to an age-dependent effect (Pollak et al. 2007). Dória et al. (2015) suggest this variant may be a risk factor for nonsyndromic hearing loss. Functional studies suggest this variant affects intercellular channels based on dye transfer assays in transiently transfected HeLa cells (D'Andrea et al. 2002; Bicego et al. 2006), although at least one study did not observe this (Oshima et al. 2003). In addition, electrical conductance was decreased to 11% of wildtype in the presence of the p.Met34Thr variant (Bicego et al. 2006). The p.Met34Thr variant is reported at a frequency of 0.03535 in the Finnish population of the 1000 Genomes Project. Based on the evidence, the p.Met34Thr variant is classified as likely pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PS1_Very strong, PS4_Strong, PM5_Moderate
Comment:
The GJB2 variant (c.101T>C; p.Met34Thr) was identified in several individuals with hearing loss and segregated in families with mild non-syndromic hearing loss (Lopponen et. al 2012; PMID 22668073) with functional studies supporting pathogenicity (Kelsell et al. 1997, PMID 9139825; Martin et al. 1999, PMID 10556284, Lopponen et. al 2012; PMID 22668073 and Shearer et al. 2014, PMID 2562649). However, this variant is quite prevalent in control databases (1049 alleles out of 122876 and 13 homozygotes in ExAC) and could be associated with reduced penetrance. Other clinical laboratories have classified this variant as pathogenic (SCV000061472 and SCV000112260) and variant of uncertain significance (SCV000193154).
Comment:
The GJB2 p.M34T variant was identified in the literature in multiple individuals with by hearing loss, and is reported as a pathogenic variant for autosomal recessive nonsyndromic hearing loss with variable expressitivity and incomplete penetrance by the ClinGen Hearing Loss Expert Panel (Coco_2013_PMID_24611097; Doria_2015; Shen_2019_PMID_31160754). The variant was also found to segregate with disease in two Portuguese compound heterozygote siblings, although the siblings exhibited different phenotypes as one exhibited profound hearing loss, while the other sibling only had moderate hearing loss (Lameiras_2015_PMID_26117665). The variant was identified in dbSNP (ID: rs35887622) and ClinVar (classified as pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel for Nonsyndromic hearing loss and deafness and 11 laboratories, as likely pathogenic by Knight Diagnostic Laboratories, as uncertain significance by Johns Hopkins and Division of Human Genetics, Children's Hospital of Philadelphia, as likely benign by Prevention Genetics, and as benign by Invitae). The variant was identified in control databases in 2538 of 282130 chromosomes (28 homozygous) at a frequency of 0.008996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 510 of 25108 chromosomes (freq: 0.02031), European (non-Finnish) in 1655 of 128490 chromosomes (freq: 0.01288), Other in 65 of 7214 chromosomes (freq: 0.00901), Ashkenazi Jewish in 82 of 10358 chromosomes (freq: 0.007917), Latino in 163 of 35426 chromosomes (freq: 0.004601) and African in 63 of 24968 chromosomes (freq: 0.002523), but was not observed in the East Asian or South Asian populations. The p.M34 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies suggest that this variant alters gap junction function in Xenopus oocytes and mammalian cells (White_1998; Skerrett_2004_PMID_ 15033936; Martin_1999_PMID_ 10556284; Thonnissen_2002_PMID_ 12189493; Bicego_2006_PMID_ 16849369; Zonta_2014_PMID_ 24624091; D’Andrea_2002_PMID_ 12176036). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The GJB2 c.101T>C variant is predicted to result in the amino acid substitution p.Met34Thr. This variant has been reported to be causative for mild to moderate autosomal recessive hearing loss with reduced penetrance (Wu et al. 2002. PubMed ID: 12172394; Bicego et al. 2006. PubMed ID: 16849369; Pollak et al. 2007. PubMed ID: 17935238; Mikstiene et al. 2016. PubMed ID: 26896187; Lameiras et al. 2015. PubMed ID: 26117665). Three other amino acid substitutions at the same position (Met34Val, Met34Leu and Met34Arg) have also been reported to be causative for hearing loss. The ClinGen Hearing Loss expert panel has classified this variant as pathogenic for autosomal recessive nonsyndromic hearing loss, noting hearing loss is typically mild with incomplete penetrance (https://www.ncbi.nlm.nih.gov/clinvar/variation/17000/; Shen et al. 2019. PubMed ID: 31160754). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as Pathogenic and reported on 02-12-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3.
Comment:
The c.101T>C (p.Met34Thr) missense variant in the GJB2gene has been previously reported in numerous individuals with autosomal recessive Nonsyndromic hearing loss and has been shown to segregate with disease (Houseman et al., 2001; Bicego et al., 2006; Löppönen et al., 2012).This variant has been observed in trans with the well-characterized GJB2 c.35delG variant (Houseman et al., 2001; Bicego et al., 2006; Pollack et al., 2007). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Martin et al., 1999; D'Andrea et al., 2002; Bicego et al., 2006). The c.101T>C variant has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC ); however, this variant has been observed as homozygous in 13 individuals in ExAC. Multiple lines of computational evidence predict a deleterious effect. In addition, multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.101T>C (p.Met34Thr) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss.
Comment:
Variant summary: GJB2 c.101T>C (p.Met34Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 1604678 control chromosomes including 26 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. c.101T>C has been well reported in the literature in studies of individuals affected with hearing loss phenotypes (example, Houseman_2001 through Shen_2019). These data indicate that the variant is likely to be associated with disease. Many publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity measured as Cx26 hemichannel activated conductance following depolarization (example, Palmada_2006). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments although a majority of these assessments support a pathogenic outcome. Furthermore, the ClinGen Hearing Loss Expert Panel has classified it as Pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance (Shen_2019). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The NM_004004.5(GJB2):c.101T>C missense variant was identified in exon 2of GJB2. This substitution is predicted to create a moderate amino acid change from a methionine to a threonine at amino acid position 34, NP_003995.2(GJB2):p.(Met34Thr). The methionine at this position has high conservation (100 vertebrates, UCSC). In silico software predictions of the pathogenicity of this variant are conflicting. It is situated in a transmembrane helix of theGJB2 protein. This variant has been observed in a population database at a frequency of 0.008% with 26 homozygotes observed (ExAC, GnomAD). However, this variant has been reported as a pathogenic variant in homozygous or compound heterozygous state, andbeen shown to segregate with disease in multiple families with hearing loss (ClinVar, Deafness variantion database, The connexin-deafness homepage). Based on current information and in association with the NM_004004.5(GJB2):c.550C>T variant, this variant has been classified as PATHOGENIC.
Comment:
The GJB2 c.101T>C (p.M34T) variant has been reported as a mild (hypomorphic) variant that leads to mild to moderate hearing loss when found in the homozygous state or in trans with a more severe pathogenic GJB2 variant (PMID: 22668073; 11134236; 20708129; 17935238).
Comment:
NM_004004.5(GJB2):c.101T>C(M34T) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 10556284, 16849369, 15033936, 9716127, 23826813 and 16380907. Classification of NM_004004.5(GJB2):c.101T>C(M34T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3, PP3.
Comment:
This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss.
Comment:
ACMG classification criteria: PS3, PS4, PM2, PP3
Comment:
GJB2 NM_004004.5 exon 2 p.Met34Thr (c.101T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with mild to severe nonsyndromic hearing loss, as well as in both affected and unaffected relatives, suggesting that this variant may have reduced penetrance or may act as a modifier of disease (Kelsell 1997 PMID:9139825, Houseman 2001 PMID:11134236, D'Andrea 2002 PMID:12176036, Feldmann 2004 PMID:14694360, Bicego 2006 PMID:16849369, Pollak 2007 PMID:17935238, Lopponen 2012 PMID:22668073, Lameiras 2015 PMID:26117665, Mikstiene 2016 PMID:26896187). This variant is also present in 2% (510/25108) of Finnish alleles in the Genome Aggregation Database, including 9 homozygotes (https://gnomad.broadinstitute.org/variant/13-20763620-A-G), which may indicate that it is a common variant or a risk allele in this population. This variant is also present in ClinVar, with classifications ranging from pathogenic to benign (Variation ID:17000). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will lead to abnormal channel function (Martin 1999 PMID:10556284, D'Andrea 2002 PMID:12176036, Bicego 2006 PMID:16849369). However, at least one study did not demonstrate this (Oshima 2003 PMID:12384501). These studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.
Comment:
This variant has required extensive investigation to determine its clinical significance. It does have high minor allele frequency in several populations (including 2.2% in the European Finnish population within ExAC). Conversely, there is significant literature evidence that this variant is pathogenic with a variable hearing phenotype.
Comment:
PP3
Comment:
This variant is one of the most common variants associated with autosomal recessive nonsyndromic hearing loss and is reported to have milder disease presentation and reduced penetrance in some families (PMID: 11134236, 16380907, 22668073). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in reduced cell to cell transfer of small molecules (PMID: 12176036, 12189493, 16300957, 16849369, 27884957).
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the GJB2 protein (p.Met34Thr). This variant is present in population databases (rs35887622, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 16077952, 22668073, 26117665; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported to show reduced penetrance (PMID: 31160754). ClinVar contains an entry for this variant (Variation ID: 17000). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The GJB2 pathogenic mild c.101T>C; p.Met34Thr variant (rs35887622) is reported in ClinVar (Variation ID: 17000), and observed in the Genome Aggregation Database with an overall allele frequency of 0.9% (2538/282130 alleles, including 28 homozygotes). This variant has been previously classified as benign based on population frequency data (Shearer 2014), and has been referred to as a variant with reduced penetrance (Feldmann 2004, Griffith 2000, Pollak 2007, Tang 2006). However, homozygosity for this variant has also been reported to co-segregate with mild to high frequency deafness (Hall 2012, Houseman 2001). Additionally, this variant has been to shown to have a variable phenotype within the same family (Lameiras 2015). Taken together, we consider this variant to be mildly pathogenic. References: Feldmann D et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004 Apr;12(4):279-84. PMID: 14694360. Griffith AJ et al. Autosomal recessive non-syndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000 Sep;67(3):745-9. PMID: 10903123. Hall A et al. Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study. BMJ Open. 2012 Jul 31;2(4). PMID: 22855627. Houseman MJ et al. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet. 2001 Jan;38(1):20-5. PMID: 11134236. Lameiras AR et al. The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. Int J Pediatr Otorhinolaryngol. 2015 Aug;79(8):1316-9. PMID: 26117665. Pollak et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007; 143A(21): 2534-2543. PMID: 17935238. Shearer AE et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53. PMID: 25262649. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22): 2401-2415. PMID: 17041943.
Comment:
The p.Met34Thr variant in GJB2 is well-established as a pathogenic variant. This variant, in homozygosity or in combination with another GJB2 variant, is commonly associated with mild to moderate hearing loss (Pollak 2007 PMID: 17935238, Snoeckx 2005 PMID: 16380907, Shen 2019 PMID: 31160754) and in rare cases, p.Met34Thr may even be associated with normal hearing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM3_VeryStrong.
Comment:
The c.101T>C (p.M34T) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the methionine (M) at amino acid position 34 to be replaced by a threonine (T). _x000D_ _x000D_ for autosomal recessive GJB2-related non-syndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related non-syndromic hearing loss and autosomal dominant GJB2-related non-syndromic hearing loss with ectodermal involvement is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.900% (2538/282130) total alleles studied. The highest observed frequency was 2.031% (510/25108) of European (Finnish) alleles. This alteration has been found to be statistically enriched in patients with non-syndromic sensorineural hearing loss and has been reported to be homozygous or compound heterozygous with a second GJB2 disease-causing allele in multiple affected individuals (Shen, 2019). In addition, this alteration has been shown to segregate with disease (Shen, 2019; Griffith, 2000). Both incomplete penetrance and and variable expressivity of hearing loss has been reported in families and individuals with this alteration and a second-disease causing allele. This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Common GJB2 variant among individuals of European background, with a carrier frequency of about 1% in Europeans (PMID: 31160754; gnomAD); Case control studies suggest this variant is associated with hearing loss; homozygous and compound heterozygous genotypes are statistically enriched in individuals with autosomal recessive nonsyndromic hearing loss compared to the general population (PMID: 31160754); Published functional studies demonstrate a dominant-negative effect leading to impaired intercellular coupling (PMID: 9139825, 10556284, 16849369); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927015.1; ClinVar; PMID: 31160754); This variant is associated with the following publications: (PMID: 21465647, 16300957, 12176036, 25262649, 15070423, 14694360, 11216656, 30094485, 30311386, 35054374, 34761457, 34697415, 22668073, 25214170, 10757647, 22975760, 22995991, 10556284, 12189493, 12384501, 20668687, 9716127, 26117665, 26896187, 11134236, 27153395, 17935238, 22567861, 10888284, 17426645, 9600457, 25388846, 22855627, 9139825, 10830906, 30609409, 29773520, 31163360, 30344259, 31827275, 31980526, 30872718, 31160754, 10903123, 23826813, 34426522, 33096615, 16077952, 33297549, 33105617, 34515852, 37838930, 36675424, 37108562, 36515421, 36048236, 16849369, 16380907, 34599368, 20083784)
Comment:
Criteria applied: PS3_MOD,PM3_VSTR,PM5_STR,PP1_VSTR,PP3
Comment:
GJB2: PM3:Very Strong, PM5, PM2:Supporting
Comment:
Across a selection of literature, the GJB2 c.101T>C (p.Met34Thr) missense variant has been identified in at least 119 patients with an autosomal recessive form of nonsyndromic hearing loss. The variant was found in a homozygous state in 35 patients, in a compound heterozygous state in 66 patients (at least 59 of whom had a pathogenic deletion), and in a heterozygous state in 18 patients (Houseman et al, 2001; Feldmann et al. 2004; Snoeckx et al. 2005; Tang et al. 2006; Pollak et al. 2007; Löppönen et al. 2012; Dória et al. 2015; Mikstiene et al. 2016). This variant is generally associated with mild to moderate nonsyndromic hearing loss, and segregation was observed in a three-generation family (Löppönen et al. 2012). The p.Met34Thr variant was detected in 66 of 5380 control chromosomes mainly in a heterozygous state, and also in family members with normal audiograms, including in two with the variant in a homozygous state, in five with the variant in a compound heterozygous state, and in 23 with the variant in a heterozygous state (Feldmann et al. 2004; Löppönen et al. 2012). This conflicting evidence may be due to reduced penetrance, estimated at 10% in one study (Pollak et al. 2007), presence of other modifying factors (Houseman et al, 2001; Bicego et al. 2006), or due to an age-dependent effect (Pollak et al. 2007). Dória et al. (2015) suggest this variant may be a risk factor for nonsyndromic hearing loss. Functional studies suggest this variant affects intercellular channels based on dye transfer assays in transiently transfected HeLa cells (D'Andrea et al. 2002; Bicego et al. 2006), although at least one study did not observe this (Oshima et al. 2003). In addition, electrical conductance was decreased to 11% of wildtype in the presence of the p.Met34Thr variant (Bicego et al. 2006). The p.Met34Thr variant is reported at a frequency of 0.03535 in the Finnish population of the 1000 Genomes Project. Based on the evidence, the p.Met34Thr variant is classified as likely pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PS1_Very strong, PS4_Strong, PM5_Moderate
Comment:
The GJB2 variant (c.101T>C; p.Met34Thr) was identified in several individuals with hearing loss and segregated in families with mild non-syndromic hearing loss (Lopponen et. al 2012; PMID 22668073) with functional studies supporting pathogenicity (Kelsell et al. 1997, PMID 9139825; Martin et al. 1999, PMID 10556284, Lopponen et. al 2012; PMID 22668073 and Shearer et al. 2014, PMID 2562649). However, this variant is quite prevalent in control databases (1049 alleles out of 122876 and 13 homozygotes in ExAC) and could be associated with reduced penetrance. Other clinical laboratories have classified this variant as pathogenic (SCV000061472 and SCV000112260) and variant of uncertain significance (SCV000193154).
Comment:
The GJB2 p.M34T variant was identified in the literature in multiple individuals with by hearing loss, and is reported as a pathogenic variant for autosomal recessive nonsyndromic hearing loss with variable expressitivity and incomplete penetrance by the ClinGen Hearing Loss Expert Panel (Coco_2013_PMID_24611097; Doria_2015; Shen_2019_PMID_31160754). The variant was also found to segregate with disease in two Portuguese compound heterozygote siblings, although the siblings exhibited different phenotypes as one exhibited profound hearing loss, while the other sibling only had moderate hearing loss (Lameiras_2015_PMID_26117665). The variant was identified in dbSNP (ID: rs35887622) and ClinVar (classified as pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel for Nonsyndromic hearing loss and deafness and 11 laboratories, as likely pathogenic by Knight Diagnostic Laboratories, as uncertain significance by Johns Hopkins and Division of Human Genetics, Children's Hospital of Philadelphia, as likely benign by Prevention Genetics, and as benign by Invitae). The variant was identified in control databases in 2538 of 282130 chromosomes (28 homozygous) at a frequency of 0.008996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 510 of 25108 chromosomes (freq: 0.02031), European (non-Finnish) in 1655 of 128490 chromosomes (freq: 0.01288), Other in 65 of 7214 chromosomes (freq: 0.00901), Ashkenazi Jewish in 82 of 10358 chromosomes (freq: 0.007917), Latino in 163 of 35426 chromosomes (freq: 0.004601) and African in 63 of 24968 chromosomes (freq: 0.002523), but was not observed in the East Asian or South Asian populations. The p.M34 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies suggest that this variant alters gap junction function in Xenopus oocytes and mammalian cells (White_1998; Skerrett_2004_PMID_ 15033936; Martin_1999_PMID_ 10556284; Thonnissen_2002_PMID_ 12189493; Bicego_2006_PMID_ 16849369; Zonta_2014_PMID_ 24624091; D’Andrea_2002_PMID_ 12176036). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The GJB2 c.101T>C variant is predicted to result in the amino acid substitution p.Met34Thr. This variant has been reported to be causative for mild to moderate autosomal recessive hearing loss with reduced penetrance (Wu et al. 2002. PubMed ID: 12172394; Bicego et al. 2006. PubMed ID: 16849369; Pollak et al. 2007. PubMed ID: 17935238; Mikstiene et al. 2016. PubMed ID: 26896187; Lameiras et al. 2015. PubMed ID: 26117665). Three other amino acid substitutions at the same position (Met34Val, Met34Leu and Met34Arg) have also been reported to be causative for hearing loss. The ClinGen Hearing Loss expert panel has classified this variant as pathogenic for autosomal recessive nonsyndromic hearing loss, noting hearing loss is typically mild with incomplete penetrance (https://www.ncbi.nlm.nih.gov/clinvar/variation/17000/; Shen et al. 2019. PubMed ID: 31160754). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as Pathogenic and reported on 02-12-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
| Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden. | Adadey SM | Life (Basel, Switzerland) | 2020 | PMID: 33126609 |
| Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. | Shen J | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31160754 |
| Study of Met34Thr variant in nonsyndromic hearing loss in four Portuguese families. | Dória M | Porto biomedical journal | 2016 | PMID: 32258544 |
| Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro. | de Wolf E | Physiological reports | 2016 | PMID: 27884957 |
| The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. | Mikstiene V | BMC genetics | 2016 | PMID: 26896187 |
| Nonsyndromic Hearing Loss and Deafness, DFNA3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2016 | PMID: 20301708 |
| Prevalence of 35delG and Met34Thr GJB2 variants in Portuguese samples. | Dória M | International journal of pediatric otorhinolaryngology | 2015 | PMID: 26482070 |
| The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. | Lameiras AR | International journal of pediatric otorhinolaryngology | 2015 | PMID: 26117665 |
| Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. | Shearer AE | American journal of human genetics | 2014 | PMID: 25262649 |
| Significance of heterozygosis M34T mutation of GJB2 gene in non-syndromic congenital deafness. Retrospective analysis of 12,472 samples of amniotic fluid. | Coco M | Journal of prenatal medicine | 2013 | PMID: 24611097 |
| Genetic mutations of GJB2 and mitochondrial 12S rRNA in nonsyndromic hearing loss in Jiangsu Province of China. | Wei Q | Journal of translational medicine | 2013 | PMID: 23826813 |
| Etiology and audiological outcomes at 3 years for 364 children in Australia. | Dahl HH | PloS one | 2013 | PMID: 23555729 |
| Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study. | Hall A | BMJ open | 2012 | PMID: 22855627 |
| Homozygous M34T mutation of the GJB2 gene associates with an autosomal recessive nonsyndromic sensorineural hearing impairment in Finnish families. | Löppönen T | Acta oto-laryngologica | 2012 | PMID: 22668073 |
| Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss. | Minárik G | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22281373 |
| Mutations of the Connexin 26 gene in families with non-syndromic hearing loss. | Al-Achkar W | Molecular medicine reports | 2011 | PMID: 21468573 |
| Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. | Teek R | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20708129 |
| Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2010 | PMID: 20083784 |
| Two novel missense mutations in the connexin 26 gene in Turkish patients with nonsyndromic hearing loss. | Yilmaz A | Biochemical genetics | 2010 | PMID: 19941053 |
| Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. | Lee KH | The Laryngoscope | 2009 | PMID: 19235794 |
| Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort. | Cama E | International journal of audiology | 2009 | PMID: 19173109 |
| Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogotá, Colombia: results of a screening program. | Tamayo ML | International journal of pediatric otorhinolaryngology | 2009 | PMID: 19027181 |
| GJB2 and mitochondrial A1555G gene mutations in nonsyndromic profound hearing loss and carrier frequencies in healthy individuals. | Baysal E | Journal of genetics | 2008 | PMID: 18560174 |
| M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. | Pollak A | American journal of medical genetics. Part A | 2007 | PMID: 17935238 |
| GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection. | Ross SA | Pediatric research | 2007 | PMID: 17426645 |
| Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. | Samanich J | American journal of medical genetics. Part A | 2007 | PMID: 17357124 |
| DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. | Tang HY | American journal of medical genetics. Part A | 2006 | PMID: 17041943 |
| Pathogenetic role of the deafness-related M34T mutation of Cx26. | Bicego M | Human molecular genetics | 2006 | PMID: 16849369 |
| Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. | Palmada M | Neurobiology of disease | 2006 | PMID: 16300957 |
| GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
| Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf. | Cheng X | American journal of medical genetics. Part A | 2005 | PMID: 16222667 |
| Dissecting clinical findings: platelet defects segregate independently of deafness and cataract in a family affected by an apparent syndromic form of macrothrombocytopenia. | Gangarossa S | International journal of molecular medicine | 2005 | PMID: 16077952 |
| GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
| Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival. | Common JE | Journal of medical genetics | 2004 | PMID: 15235031 |
| Molecular epidemiology of DFNB1 deafness in France. | Roux AF | BMC medical genetics | 2004 | PMID: 15070423 |
| Aberrant gating, but a normal expression pattern, underlies the recessive phenotype of the deafness mutant Connexin26M34T. | Skerrett IM | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2004 | PMID: 15033936 |
| Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. | Feldmann D | European journal of human genetics : EJHG | 2004 | PMID: 14694360 |
| Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10. | Zoll B | Human mutation | 2003 | PMID: 12497637 |
| Roles of Met-34, Cys-64, and Arg-75 in the assembly of human connexin 26. Implication for key amino acid residues for channel formation and function. | Oshima A | The Journal of biological chemistry | 2003 | PMID: 12384501 |
| Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. | Thönnissen E | Human genetics | 2002 | PMID: 12189493 |
| Hearing loss: frequency and functional studies of the most common connexin26 alleles. | D'Andrea P | Biochemical and biophysical research communications | 2002 | PMID: 12176036 |
| Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. | Marlin S | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11493200 |
| Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. | Houseman MJ | Journal of medical genetics | 2001 | PMID: 11134236 |
| The M34T allele variant of connexin 26. | Cucci RA | Genetic testing | 2000 | PMID: 11216656 |
| Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. | Griffith AJ | American journal of human genetics | 2000 | PMID: 10903123 |
| High frequency hearing loss correlated with mutations in the GJB2 gene. | Wilcox SA | Human genetics | 2000 | PMID: 10830906 |
| Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family. | Kelsell DP | European journal of human genetics : EJHG | 2000 | PMID: 10757647 |
| Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness. | Martin PE | Human molecular genetics | 1999 | PMID: 10556284 |
| Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. | Green GE | JAMA | 1999 | PMID: 10376574 |
| Connexin mutations in deafness. | White TW | Nature | 1998 | PMID: 9716127 |
| Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. | Scott DA | Human mutation | 1998 | PMID: 9600457 |
| Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. | Kelley PM | American journal of human genetics | 1998 | PMID: 9529365 |
| Connexin mutations and hearing loss. | Scott DA | Nature | 1998 | PMID: 9422505 |
| Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. | Kelsell DP | Nature | 1997 | PMID: 9139825 |
| Palmoplantar keratoderma, deafness and atopy. | Verbov J | The British journal of dermatology | 1987 | PMID: 2956987 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e8b1ce82-bc97-4baf-b442-294c2a6849cd | - | - | - | - |
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Text-mined citations for rs35887622 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.