Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000428254 | SCV000521130 | likely pathogenic | not provided | 2017-02-01 | criteria provided, single submitter | clinical testing | The M46T variant in the ACTA1 gene has been reported previously using alternate nomenclature (M44T) in association with nemaline myopathy (Laing et al., 2009). The M46T variant was not observed in approximately 6,500 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 M46T 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. In addition, 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. Missense variants in nearby residues (H42Y, Q43R, G44V, V45F, G48S, G48C, G48D, M49V, and G50C) have been reported in the Human Gene Mutation Database in association with ACTA1-related myopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. The M46T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV002519526 | SCV003524126 | pathogenic | Actin accumulation myopathy | 2022-08-26 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the ACTA1 protein (p.Met46Thr). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 381642). This variant is also known as p.M44T. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy (PMID: 19562689). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). |