ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 227 of the GCDH protein (p.Arg227Trp). This variant is present in population databases (rs368357056, gnomAD 0.007%). This missense change has been observed in individual(s) with glutaric acidemia type I (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: 658536). 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 not expected to disrupt GCDH protein function with a negative predictive value of 80%. This variant disrupts the p.Arg227 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9266361, 10066389, 10960496, 11073722, 22728054, 23395213, 28438223). 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.