ClinVar

Description

Variant summary: GJB2 c.533T>C (p.Val178Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251290 control chromosomes. c.533T>C has been reported in the literature as a homozygous/compound heterozygous genotype in cohorts of individuals affected with hearing impairment and/or sensorineural hearling loss (SNHL) (example, Hamelmann_2001, Tang_2006, Kabahuma_2011, Neocleous_2014). These data indicate that the variant is very likely to 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. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.