ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 949 of the PEX1 protein (p.Arg949Gln). This variant is present in population databases (rs61750425, gnomAD 0.007%). This missense change has been observed in individuals with a Zellweger syndrome spectrum disorder (PMID: 11389485, 21031596, 31964843; Invitae). ClinVar contains an entry for this variant (Variation ID: 556176). 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 PEX1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg949 amino acid residue in PEX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21031596, 21844578, 27469511). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.