ACTA1 p.Glu336Ala

The c.1007A>C (NM_001100.4(ACTA1):c.1007A>C (p.Glu336Ala)) variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 336 (p.Glu336Ala). This variant is absent from gnomAD v4.1.0 (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 disease (PP2). The computational predictor REVEL gives a score of 0.874, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). At least one patient with this variant displayed cores and fiber type disproportion on muscle biopsy, which is highly specific for actin accumulation myopathy (PP4_Moderate, PMID: 15520409). This variant has been reported in 5 individuals from one family with muscle weakness (PP1_Moderate; PMID: 15520409). 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, PP2, PP3, PP4_Moderate, PP1_Moderate (Congenital Myopathies VCEP Specifications Version 2.0; July 8, 2024).