ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the PEX6 protein (p.Arg601Gln). This variant is present in population databases (rs34324426, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset Zellweger spectrum disorder, also called Heimler syndrome (PMID: 25079599, 26387595, 27302843, 29676688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198709). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PEX6 function (PMID: 26387595). This variant disrupts the p.Arg601 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 26287655), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.