ClinVar

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 143 of the PAH protein (p.Asp143Val). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of phenylketonuria and/or hyperphenylalaninemia (PMID: 27469133, 31332730, 32668217). ClinVar contains an entry for this variant (Variation ID: 1510805). 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 PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Asp143 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8889583, 18937047, 21147011, 21953985). 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.