rs755165065

Description

The E644K variant in the POLR3A gene has been reported previously in three unrelated patients with hypomyelinating leukodystrophy who were heterozygous for the E644K variant and heterozygous for another variant (Wolf et al., 2014). The E644K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E644K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The E644K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 644 of the POLR3A protein (p.Glu644Lys). This variant is present in population databases (rs755165065, gnomAD 0.002%). This missense change has been observed in individuals with POLR3-related leukodystrophy (PMID: 25339210). ClinVar contains an entry for this variant (Variation ID: 372801). 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 tolerated. 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.