ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 178 of the HEXA protein (p.Arg178Cys). This variant is present in population databases (rs121907953, gnomAD 0.004%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 2137287, 27896118). ClinVar contains an entry for this variant (Variation ID: 3897). 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 HEXA protein function. Experimental studies have shown that this missense change affects HEXA function (PMID: 2137287). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg178 amino acid residue in HEXA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10584247, 14577003, 16088929, 17015493). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.