ClinVar

Description

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 48 of the SOD1 protein (p.Val48Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 30637102, 32166880, 34404558). ClinVar contains an entry for this variant (Variation ID: 1018905). 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 SOD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Val48 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been observed in individuals with SOD1-related conditions (PMID: 25729540), which suggests that this may be a clinically significant amino acid residue. 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.