The NM_001100.4(ACTA1):c.687G>A variant in ACTA1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 229 (p.Met229Ile, also known as p.Met227Thr). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.842, 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). Different missense variants (c.686T>C (p.Met229Thr), c.685A>T (p.Met229Leu) and c.685A>G (p.Met229Val)) in the same codon have been classified as pathogenic/ likely pathogenic for alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5_Strong; SCV007612356.1, SCV007612355.1, SCV007612357.1). This variant has been reported in two probands with clinical features of congenital myopathies, of which one was a de novo case with confirmed parental relationship (PS4_Supporting, PS2_Moderate; PMID: 38544359, 12921789). 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, PP3, PP2, PM5_Strong, PS4_Supporting, PS2_Moderate (ClinGen Congenital Myopathies VCEP specifications version 2.0)