The c.1071G>C variant in ACTA1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 357 (legacy nomenclature: p.Met355Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 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). This variant has been reported in 2 adult probands with features of muscle weakness (PS4_Supporting; Invitae, SCV001199812.3, GeneDx, SCV001989742.1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024).