ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.246C>G (p.Ile82Met)
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.246C>G (p.Ile82Met)
Variation ID: 188756 Accession: VCV000188756.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189336 (GRCh38) [ NCBI UCSC ] 13: 20763475 (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 Mar 29, 2015 Feb 14, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.246C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Ile82Met missense NC_000013.11:g.20189336G>C NC_000013.10:g.20763475G>C NG_008358.1:g.8640C>G LRG_1350:g.8640C>G LRG_1350t1:c.246C>G LRG_1350p1:p.Ile82Met - Protein change
- I82M
- Other names
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- Canonical SPDI
- NC_000013.11:20189335:G:C
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 |
561 | 627 |
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
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2019 | RCV000169070.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 29, 2023 | RCV001207124.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257041.1 | |
GJB2-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2023 | RCV004528922.2 |
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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Pathogenic
(Aug 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001433546.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.246C>G, p.Ile82Met is only present in european non-finish population with a filtering variant … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.246C>G, p.Ile82Met is only present in european non-finish population with a filtering variant frequency of 0,00031% from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) meeting PM2. This variant was identified in trans with several pathogenic variants at least four times applying to PM3_VeryStrong (PMID:15964725,16380907,12112666). Besides, p.Ile82Met change in trans with c.35delG variant segregated in two affected meeting PP1_Moderate criteria (PMID: 12112666). Computational evidence showed a damage impact of the mutation to the protein (REVEL: 0.928) meeting PP3 rule. Functional studies in Xenopus Laevis oocytes demonstrated a deleterious effect since there was a significantly decrease of current measure when p.Ile82Met was injected compared to wild type channels (PMID: 16300957) applying to PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP1_Moderate, PM3_VeryStrong, PP3 and PS3_Moderate). (less)
Number of individuals with the variant: 1
Clinical Features:
Prelingual severe bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
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Likely pathogenic
(Sep 21, 2023)
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criteria provided, single submitter
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: SCV004103564.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GJB2 c.246C>G variant is predicted to result in the amino acid substitution p.Ile82Met. This variant was reported in at least two individuals with autosomal … (more)
The GJB2 c.246C>G variant is predicted to result in the amino acid substitution p.Ile82Met. This variant was reported in at least two individuals with autosomal recessive nonsyndromic hearing loss in the compound heterozygous state along with a second pathogenic variant (Kupka. 2002. PubMed ID: 12112666; Dalamón. 2005. PubMed ID: 15964725). In vitro experiments demonstrated this variant impairs protein function (Palmada. 2005. PubMed ID: 16300957). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763475-G-C). This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Mar 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360719.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GJB2 c.246C>G (p.Ile82Met) results in a conservative amino acid change located in the transmembrane domain (Palmada 2006) of the encoded protein sequence. Four … (more)
Variant summary: GJB2 c.246C>G (p.Ile82Met) results in a conservative amino acid change located in the transmembrane domain (Palmada 2006) 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 8.1e-06 in 246170 control chromosomes (gnomAD). c.246C>G has been reported in the literature in multiple compound heterozygous individuals affected with Non-Syndromic Hearing Loss (Kupka 2002, Bartsch 2010, Danilenko 2012, Snoeckx 2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating profound reduction in channel activity as determined by electrophysiological analysis on Xenopus oocytes expressing the mutant protein (Palmada 2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 06, 2021)
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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: SCV001767244.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Published functional studies demonstrate a damaging effect on protein function due to a reduction of channel activation and possible dominant negative effect on wild-type protein … (more)
Published functional studies demonstrate a damaging effect on protein function due to a reduction of channel activation and possible dominant negative effect on wild-type protein (Palmada et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 20234132, 15964725, 19887791, 16380907, 25388846, 12112666, 16300957) (less)
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Likely pathogenic
(Apr 10, 2014)
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criteria provided, single submitter
Method: literature only
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220237.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 29, 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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Invitae
Accession: SCV001378464.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the GJB2 protein (p.Ile82Met). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the GJB2 protein (p.Ile82Met). This variant is present in population databases (rs781534323, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 12112666, 15964725, 20234132, 22567152). ClinVar contains an entry for this variant (Variation ID: 188756). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 16300957). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 27, 2021)
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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: SCV002086060.1
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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Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus. | Danilenko N | PloS one | 2012 | PMID: 22567152 |
GJB2 mutations and genotype-phenotype correlation in 335 patients from germany with nonsyndromic sensorineural hearing loss: evidence for additional recessive mutations not detected by current methods. | Bartsch O | Audiology & neuro-otology | 2010 | PMID: 20234132 |
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 |
Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients. | Dalamón V | Hearing research | 2005 | PMID: 15964725 |
Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. | Kupka S | Human mutation | 2002 | PMID: 12112666 |
Text-mined citations for rs781534323 ...
HelpRecord last updated Jul 23, 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.