The NM_001100.4(ACTA1):c.39C>A variant in ACTA1 is a missense variant predicted to cause a substitution of aspartate by glutamate at amino acid 13 (p.Asp13Glu). This variant is absent from gnomAD v4.1.1 (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 dominant disease (PP2). The computational predictor REVEL gives a score of 0.903, which is above the threshold of 0.7, so evidence does correlate with impact on ACTA1 function (PP3). This variant has been observed in the heterozygous state in two individuals with progressive cardiomyopathy (requiring transplantation in one) and milder muscle weakness, one of which was confirmed de novo (PS2, PS4_Supporting; Labcorp Genetics SCV001395135.7, GeneDx SCV001823123.1). Additionally, the variant segregated with disease in two individuals from one family (PP1_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PP1_Moderate, PS4_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2.0).