The NM_001100.4(ACTA1):c.668T>C variant in ACTA1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 223 (p.Leu223Pro). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.944, 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 observed in the heterozygous state in at least five individuals with features of congenital myopathies, of which two were de novo with unconfirmed parental relationships (PS4_Supporting, PM6; PMID: 15468086, 24642510, 38093364, 34671977, 20179953). Immunological staining of NIH3T3 fibroblasts showed phalloidin negative nemaline rods and aggregates in the cytoplasm diffuse cytoplasmic myc-actin staining indicating that this variant impacts protein function (PS3_Supporting; PMID: 19206168). 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, PS4_Supporting, PM6, PS3_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2.0)