ACTA1 p.Pro334Arg

The c.1001C>G variant in ACTA1 is a missense variant predicted to cause a substitution of proline by arginine at amino acid position 334. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.7 set by the CM VCEP (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 one individual and as a de novo occurrence with unconfirmed parental relationships in one individual with alpha-actinopathy (PS4_Supporting, PS2; Invitae internal data; PMID: 19562689,). Another missense variant c.1000C>T, p.Pro334Ser (PMID: 15468086) in the same codon has been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). 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, PM5, PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024).