ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.110T>C (p.Val37Ala)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.110T>C (p.Val37Ala)
Variation ID: 449490 Accession: VCV000449490.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189472 (GRCh38) [ NCBI UCSC ] 13: 20763611 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 19, 2017 Feb 14, 2024 Jul 28, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6(GJB2):c.110T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.6:c.110T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val37Ala missense NC_000013.11:g.20189472A>G NC_000013.10:g.20763611A>G NG_008358.1:g.8504T>C LRG_1350:g.8504T>C LRG_1350t1:c.110T>C LRG_1350p1:p.Val37Ala - Protein change
- V37A
- Other names
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- Canonical SPDI
- NC_000013.11:20189471:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
556 | 617 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 20, 2024 | RCV000520583.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2019 | RCV000826112.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Feb 24, 2021 | RCV000855645.4 | |
Likely pathogenic (1) |
reviewed by expert panel
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Jul 28, 2020 | RCV001252676.1 |
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
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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
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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
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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. |
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Likely pathogenic
(Jul 28, 2020)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001428435.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Comment:
The allele frequency of the p.Val37Ala variant in the GJB2 gene is 0.04% (13/35428) of Latino chromosomes by gnomAD v2.1.1, which is a low enough … (more)
The allele frequency of the p.Val37Ala variant in the GJB2 gene is 0.04% (13/35428) of Latino chromosomes by gnomAD v2.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been identified in 3 heterozygous individuals with hearing loss who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (PM3; Partners LMM internal data SCV000967620.2). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). A different pathogenic missense variant (p.Val37Ile) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; p.Val37Ile ClinVar Variation ID 17023, PMID 31160754). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3, PM5, PM2_Supporting, PP3). (less)
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Likely pathogenic
(Mar 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967620.2
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Val37Ala variant in GJB2 has been previously reported in several individuals with hearing loss in whom a second GJB2 variant was not identified. However, … (more)
The p.Val37Ala variant in GJB2 has been previously reported in several individuals with hearing loss in whom a second GJB2 variant was not identified. However, this variant has also been identified by our laboratory in one individual with hearing loss who carried a second pathogenic GJB2 variant. This variant has been identified in 0.036% (13/35428) of Latino chromosomes and in 0.36% (9/24968) of African by gnomAD (http://gnomad.broadinstitute.org), which are low enough to be consistent with recessive carrier frequencies. Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, a pathogenic (p.Val37Ile) and likely pathogenic (p.Val37Phe) at the same amino acid residue have been previously reported in individuals with hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3, PM5, PM2_Supporting, PP3. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 24, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698224.3
First in ClinVar: Dec 19, 2017 Last updated: Aug 08, 2020 |
Comment:
Variant summary: GJB2 c.110T>C (p.Val37Ala) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four … (more)
Variant summary: GJB2 c.110T>C (p.Val37Ala) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (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 7.6e-05 in 250894 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (7.6e-05 vs 0.025), allowing no conclusion about variant significance. c110T>C has been reported in the literature in individuals affected with congenital deafness (Azaiez_2004), non-syndromic sensorineural hearing loss (Lipan_2011), moderate hearing loss (Putcha_2007) and sensorineural hearing loss (Gruber_2016). A second variant in the GJB2 gene was not identified in the individuals reported in these studies, however the variant was reported to co-occur with a GJB6 variant (c.631T>G, p.C211G) of unknown pathogenicity in one patient (Putcha_2007). In addition, one Clinvar submitter reports that this variant has been detected in trans with a second pathogenic GJB2 variant in an individual with hearing loss tested at their facility. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Oct 10, 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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GeneDx
Accession: SCV000617689.6
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
Observed heterozygous with no other GJB2 variants in patients with hearing loss in published literature (Azaiez et al., 2004; Putcha et al., 2007; Lipan et … (more)
Observed heterozygous with no other GJB2 variants in patients with hearing loss in published literature (Azaiez et al., 2004; Putcha et al., 2007; Lipan et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 21287563, 25087612, 27466889, 15365987, 17666888) (less)
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Likely pathogenic
(Jan 20, 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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Invitae
Accession: SCV004309301.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ala). This variant is present in population databases (rs141774369, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15365987, 17666888). ClinVar contains an entry for this variant (Variation ID: 449490). 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%. This variant disrupts the p.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15365987, 17666888). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Mar 09, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086066.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The Yield of Multigene Testing in the Management of Pediatric Unilateral Sensorineural Hearing Loss. | Gruber M | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2016 | PMID: 27466889 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. | Lipan M | The Laryngoscope | 2011 | PMID: 21287563 |
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. | Putcha GV | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17666888 |
GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1d8c5ad9-8453-4ae4-8c22-1b4c7b044189 | - | - | - | - |
Text-mined citations for rs141774369 ...
HelpRecord last updated Feb 20, 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.