ClinVar Miner

Submissions for variant NM_004004.5(GJB2):c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC (p.Val198Glnfs) (rs111033335)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211782 SCV000061528 pathogenic Rare genetic deafness 2015-04-27 criteria provided, single submitter clinical testing The p.Val198fs variant in GJB2 has been reported in 3 individuals with hearing l oss (Tang 2006, Chan 2010, LMM unpublished data), 2 of whom were compound hetero zygous with a second pathogenic or likely pathogenic GJB2 variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 198 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic for hearing loss in an autosomal recessive manner ( org/personalizedmedicine/LMM) based on the predicted impact of the variant and m ultiple occurrences with pathogenic GJB2 variants in individuals with hearing lo ss.
Genetic Services Laboratory, University of Chicago RCV000037866 SCV000247477 pathogenic Deafness, autosomal recessive 1A 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727541 SCV000709616 pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037866 SCV000919426 likely pathogenic Deafness, autosomal recessive 1A 2018-09-27 criteria provided, single submitter clinical testing Variant summary: GJB2 c.592_600delinsCAGTGTTCATGACATTC (p.Val198GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg216fsX17). The variant was absent in 246636 control chromosomes (gnomAD and publication data). c.592_600delinsCAGTGTTCATGACATTC has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (Tang 2006, Chan 2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678892 SCV000805085 pathogenic Hearing loss 2010-03-31 no assertion criteria provided clinical testing

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