ClinVar

Description

Variant summary: GJB2 c.551G>A (p.Arg184Gln) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 254160 control chromosomes (gnomAD). c.551G>A has been reported in the literature in multiple individuals affected with Autosomal Dominant Non-Syndromic Hearing Loss and the variant segregated with the disease (examples: Hamelmann_2001, Hwa_2003, Putcha_2007, Su_2010 and delaLuzArenas-Sordo_2012). The variant has also been identified in multiple individuals as a de novo occurrence (examples: Huang_2011 and Mahdieh_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed a dominant negative effect on both connexin 26 and connexin 30 (example: Su 2010). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic (n=8) and likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.