ACTA1 p.Pro334Ser

The c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24).