ClinVar

Description

Variant summary: GJB2 c.257C>G (p.Thr86Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of 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 4e-06 in 251278 control chromosomes (gnomAD). c.257C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Hearing Loss (e.g. Ohtsuka_2003, Choi_2009, Huang_2013, Xu_2014). These data indicate that the variant is very likely to be associated with disease. When expressed alone in HEK293 cells, the variant protein failed to form gap junctions and had deficient hemichannel opening (Choi_2009). This deficiency was rescued when the variant was co-expressed with WT-GJB2, supporting the recessive nature of this specific variant. The following publications have been ascertained in the context of this evaluation (PMID: 19384972, 23266159, 12560944, 24941117). Six ClinVar submitters have assessed this variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.