ClinVar

Description

This sequence change replaces arginine with tryptophan at codon 159 of the BCKDHA protein (p.Arg159Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs769688327, ExAC 0.002%). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 8161368, 28830848). This variant is also known as R114W. ClinVar contains an entry for this variant (Variation ID: 553759). 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 BCKDHA protein function. Experimental studies have shown that this variant affects BCKDHA protein function (PMID: 11069910). This variant disrupts the p.Arg159 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26257134, 31980395). 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.