ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.583A>G (p.Met195Val)
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.583A>G (p.Met195Val)
Variation ID: 225375 Accession: VCV000225375.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20188999 (GRCh38) [ NCBI UCSC ] 13: 20763138 (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 May 25, 2017 Mar 16, 2024 Jul 15, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6(GJB2):c.583A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.6:c.583A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met195Val missense NC_000013.11:g.20188999T>C NC_000013.10:g.20763138T>C NG_008358.1:g.8977A>G LRG_1350:g.8977A>G LRG_1350t1:c.583A>G LRG_1350p1:p.Met195Val - Protein change
- M195V
- Other names
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- Canonical SPDI
- NC_000013.11:20188998:T: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
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 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 |
556 | 619 |
Conditions - Germline
Condition
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Mar 18, 2016 | RCV000490342.1 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2023 | RCV000505510.3 | |
Likely pathogenic (1) |
reviewed by expert panel
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Jul 15, 2020 | RCV001252673.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2023 | RCV001853385.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV002283467.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV003897461.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2021 | RCV002503834.1 |
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
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
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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 15, 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: SCV001428432.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Comment:
The c.583A>G (p.Met195Val) variant in GJB2 was present in 0.000074% (4/18394, CI 95%) of East Asisan alleles in gnomAD v2.1.1 and was absent from gnomAD … (more)
The c.583A>G (p.Met195Val) variant in GJB2 was present in 0.000074% (4/18394, CI 95%) of East Asisan alleles in gnomAD v2.1.1 and was absent from gnomAD v3 (PM2). This variant has been identified in 3 probands with hearing loss in whom another pathogenic or suspected-pathogenic variant was found in trans (PM3_Strong; PMID: 24013081, 20497192, 30146550). It has also been identified in several probands with hearing loss in whom a second variant was not identified (PMID: 23555729, 19366456, 19125024, 27627659, 24507663). The REVEL computational prediction tool produced a score of 0.962, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3_Strong, PP3). (less)
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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Autosomal dominant nonsyndromic hearing loss 3A
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267341.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(May 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599761.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572518.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common … (more)
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26749107). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225375). The variant has been observed in at least four similarly affected unrelated individuals (PMID: 19125024, 19366456, 21366436, 23555729). A different missense change at the same codon (p.Met195Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438621 , VCV001334161 , VCV001479826). The variant is in trans with the other pathogenic variants (PMID: 19125024,24507663,30146550). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Likely pathogenic
(Oct 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809846.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
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Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935279.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
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Pathogenic
(Oct 27, 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: SCV002243189.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Val). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Val). This variant is present in population databases (rs532203068, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive GJB2-related conditions (PMID: 20497192, 24013081, 30146550, 33597575). This variant has been reported in individual(s) with autosomal dominant GJB2-related conditions (PMID: 19125024, 19366456, 21366436, 23555729); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 225375). 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: 26749107). This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 10, 2024)
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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: SCV004714870.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GJB2 c.583A>G variant is predicted to result in the amino acid substitution p.Met195Val. This variant has been reported in the compound heterozygous state in … (more)
The GJB2 c.583A>G variant is predicted to result in the amino acid substitution p.Met195Val. This variant has been reported in the compound heterozygous state in multiple individuals with hearing loss (Tsukada. 2010. PubMed ID: 20497192; Wang. 2021. PubMed ID: 33597575; Minami. 2013. PubMed ID: 24013081). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD and is interpreted as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/225375/). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Oct 06, 2017)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800789.2
First in ClinVar: Sep 19, 2017 Last updated: Dec 23, 2019 |
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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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Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach. | Wang J | Scientific reports | 2021 | PMID: 33597575 |
Children with GJB2 gene mutations have various audiological phenotypes. | Wang X | Bioscience trends | 2018 | PMID: 30146550 |
Social Health Insurance-Based Simultaneous Screening for 154 Mutations in 19 Deafness Genes Efficiently Identified Causative Mutations in Japanese Hearing Loss Patients. | Mori K | PloS one | 2016 | PMID: 27627659 |
The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. | Kim HR | Human genetics | 2016 | PMID: 26749107 |
Deafness gene variations in a 1120 nonsyndromic hearing loss cohort: molecular epidemiology and deafness mutation spectrum of patients in Japan. | Nishio SY | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25788563 |
Identification of both MT-RNR1 m.1555A>G and bi-allelic GJB2 mutations in probands with non-syndromic hearing loss. | Chai Y | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24507663 |
GJB2-associated hearing loss undetected by hearing screening of newborns. | Minami SB | Gene | 2013 | PMID: 24013081 |
Etiology and audiological outcomes at 3 years for 364 children in Australia. | Dahl HH | PloS one | 2013 | PMID: 23555729 |
GJB2 allele variants and the associated audiologic features identified in Chinese patients with less severe idiopathic hearing loss. | Zhang J | Genetic testing and molecular biomarkers | 2011 | PMID: 21366436 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. | Dai P | Journal of translational medicine | 2009 | PMID: 19366456 |
Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling. | Batissoco AC | Ear and hearing | 2009 | PMID: 19125024 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/956244b5-ee05-47cd-98e0-a3c8fa5f5bc9 | - | - | - | - |
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Text-mined citations for rs532203068 ...
HelpRecord last updated Mar 17, 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.