ClinVar

Description

This sequence change replaces glycine with arginine at codon 48 of the ACTA1 protein (p.Gly48Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. 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 ACTA1 protein function. This variant disrupts the p.Gly48 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19562689, 26172852, 27447704; Invitae). 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.