ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.583A>G (p.Met195Val)

gnomAD frequency: 0.00001  dbSNP: rs532203068
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001252673 SCV001428432 likely pathogenic Nonsyndromic genetic hearing loss 2020-07-15 reviewed by expert panel curation 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).
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000490342 SCV000267341 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A; Autosomal dominant nonsyndromic hearing loss 3A 2016-03-18 criteria provided, single submitter reference population
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000505510 SCV000599761 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
Invitae RCV001853385 SCV002243189 pathogenic not provided 2023-10-27 criteria provided, single submitter clinical testing 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.
3billion RCV002283467 SCV002572518 pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2022-09-01 criteria provided, single submitter clinical testing 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.
Fulgent Genetics, Fulgent Genetics RCV002503834 SCV002809846 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher 2021-10-22 criteria provided, single submitter clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland RCV000505510 SCV003935279 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2023-06-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004530262 SCV004714870 likely pathogenic GJB2-related disorder 2024-01-10 criteria provided, single submitter clinical testing 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.
Counsyl RCV000505510 SCV000800789 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-10-06 no assertion criteria provided clinical testing

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