ACTA1 p.Pro334Leu

The c.1001C>T (NM_001100.4(ACTA1):c.1001C>T (p.Pro334Leu)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 334 (p.Pro334Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.814, 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). Another missense variant p.Pro334Arg (c.1001C>G) [ClinVar Variation ID: 1031829] in the same codon has been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5_supporting). This variant has been identified in 4 probands with autosomal dominant alpha-actinopathy. At least one patient with this variant displayed rods on a muscle biopsy, which is highly specific for alpha-actinopathy (PS4_moderate, PP4_moderate; Invitae, Paris-East Créteil University internal data, Alan Beggs personal communication, LOVD). Of note, all probands displayed later than typical onset of symptoms with onset ranging from late teens to the 5th or 6th decade of life. 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_supporting, PS4_moderate, PP4_moderate (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 9/9/2024).