The NM_001100.4:c.1075A>C variant in ACTA1 is a missense variant predicted to cause substitution of isoleucine by leucine at amino acid 359. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.865, 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 identified as a de novo occurrence with confirmed parental relationships in 1 individual with autosomal dominant alpha-actinopathy (PS2; PMID: 11333380). At least one patient with this variant displayed nemaline bodies and intranuclear rods, which is highly specific for autosomal dominant alpha-actinopathy (PP4_Moderate, PMID: 11333380). Actin localization in patient muscle biopsies showed abnormal localization of actin indicating that this variant impacts protein function (PMID: 11333380). Actin polymerization in expressed α-skeletal-muscle actins (wild-type and mutants) as 35S-labeled proteins by in vitro transcription translation reactions in reticulocyte lysate showed impaired co-polymerization of I357L actin with wild-type rabbit α-skeletal-muscle actin indicating that this variant impacts protein function (PMID:15226407) (PS3_Moderate). 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: PS2, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; July 8th, 2024)