The NM_001100.4(ACTA1):c.686T>G variant in ACTA1 is a missense variant predicted to cause substitution of methionine by arginine at amino acid 229 (p.Met229Arg). This variant is absent from gnomAD v.4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the VCEP 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). Three missense variants, [c.686T>C (p.Met229Thr), c.685A>T (p.Met229Leu), and c.685A>G (p.Met229Val); SCV007612356.1, SCV007612355.1, SCV007612357.1, respectively] in the same codon have been classified as pathogenic or likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5_Strong). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with features of ACTA1-related myopathy including proximal myopathy and delayed onset of walking (PM6_Supporting; VCEP internal contributor). 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: PM2_Supporting, PP3, PP2, PM5_Strong, PM6_Supporting (ClinGen Congenital Myopathies VCEP Specifications Version 2.0).