ClinVar

Description

This variant disrupts the p.Tyr211 amino acid residue in GJB1. Other variant(s) that disrupt this residue (p.Tyr211His) have been observed in individuals with GJB1-related conditions (PMID: 11140841, 17100997), which suggests that this may be a clinically significant amino acid residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with Charcot-Marie-Tooth in a family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 211 of the GJB1 protein (p.Tyr211Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.