ClinVar

Description

This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Thr154 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been observed in individuals with GJA1-related conditions (PMID: 16813608, 17509830, 19338053, 29927410), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJA1 protein function. This missense change has been observed in individuals with clinical features of autosomal dominant oculodentodigital dysplasia (PMID: 16813608; Invitae). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 154 of the GJA1 protein (p.Thr154Asn).