ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 390 of the NME8 protein (p.Arg390Thr). This variant is present in population databases (rs202221051, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NME8-related conditions. ClinVar contains an entry for this variant (Variation ID: 863904). 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 NME8 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.