ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 208 of the ACAT1 protein (p.Arg208Gln). This variant is present in population databases (rs370720208, gnomAD 0.003%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 17236799; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198381). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 17236799). This variant disrupts the p.Arg208 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been observed in individuals with ACAT1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.