ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.269dup (p.Val91fs) (rs730880338)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211771 SCV000204010 pathogenic Rare genetic deafness 2015-04-07 criteria provided, single submitter clinical testing The p.Val91fs (c.269_270insT) variant in GJB2 has been reported in over 10 indiv iduals with hearing loss who were homozygous or compound heterozygous for a know n pathogenic variant (Dahl 2013, Dalamon 2013, Denoyelle 1999, Gravina 2010, Gre en 1999, Pandya 2003, Preciado 2004, Propst 2006, Siem 2010, Snoeckx 2005). Thi s variant has been identified in 2/66710 of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org); though this frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 91 and leads to a premature termination codon 11 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GJB2 gene is an establish ed disease mechanism in autosomal recessive sensorineural hearing loss. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal re cessive hearing loss based on predicted impact to the protein and prior reports of the variant in trans with a known pathogenic variant. ACMG/AMP Criteria appli ed: PVS1, PM3_VeryStrong, PM2.
Integrated Genetics/Laboratory Corporation of America RCV000154347 SCV000698240 pathogenic Deafness, autosomal recessive 1A 2016-06-23 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.269dupT (p.Val91Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 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. c.290dupA, c.298delC, and c.313_326delAAGTTCATCAAGGG). This variant was observed in the large, broad control population, ExAC, with an allele frequency of 2/121348 (1/60674), which does not exceed the estimated maximal expected allele frequency for a pathogenic GJB2 variant of 1/40 (0.025). The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Counsyl RCV000154347 SCV000220877 pathogenic Deafness, autosomal recessive 1A 2018-03-09 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678876 SCV000805069 pathogenic Hearing loss 2015-12-17 no assertion criteria provided clinical testing

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