ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 853 of the POLG protein (p.Arg853Trp). This variant is present in population databases (rs121918053, gnomAD 0.003%). This missense change has been observed in individual(s) with early-onset Parkinson disease and/or progressive external ophthalmoplegia and ptosis (PMID: 16401742, 16634032, 27185166). ClinVar contains an entry for this variant (Variation ID: 13512). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). This variant disrupts the p.Arg853 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18546365, 19478085, 20185557). 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.