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 variant disrupts the p.Gly188 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17557229, 22526846, 29499199). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces glycine with serine at codon 188 of the PAH protein (p.Gly188Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. 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.