ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.516G>C (p.Trp172Cys) (rs1302739538)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004778 SCV001164260 pathogenic Nonsyndromic hearing loss and deafness 2019-07-28 reviewed by expert panel curation The p.Trp172Cys variant in the GJB2 gene was absent from gnomAD (PM2). However, this variant has been identified at an allele frequency of 1.9% (6/314) in unaffected Tuvinian individuals (PMID: 20201936). This frequency would normally lead to application of BA1 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, the variant was found to have a statistically higher prevalence in affected Tuvinian individuals (66/440 alleles) over ethnically-matched controls (6/314 alleles) (15% vs 1.9%; p<0.0001, PS4; PMID: 20201936) suggesting that this is actually a high frequency founder variant in this population. This variant has been detected in trans with two pathogenic variants in probands with hearing loss (PM3_supporting PMID:20201936; 15790391). The p.Trp172Cys variant in GJB2 has been reported to segregate with hearing loss in at least 9 affected family members (PP1_Strong; PMID: 20201936). The REVEL computational prediction analysis tool produced a score of 0.7 (rounded up from 0.687), which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PS4, PP1_Strong, PP3, PM3_supporting).
Laboratory of Human Molecular Genetics,Institute of Cytology and Genetics RCV000721943 SCV000852065 likely pathogenic Deafness, autosomal recessive 1A no assertion criteria provided research

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