ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 224 of the PAH protein (p.Ile224Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a positive newborn screening result for PAH-related disease (PMID: 30747360). 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. This variant disrupts the p.Ile224 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32668217). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.