ACTA1 p.Cys376Phe

The variant NM_001100.4:c.1127G>T in ACTA1 is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 376 (p.Cys376Phe) in exon 7/7. The variant is absent from gnomAD v4.1.1 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.955, which is above the threshold necessary to apply PP3. In addition, 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 reported as a de novo observation with confirmed parental relationships in one proband with features associated with congenital myopathy which meets the criteria for PS2 (Invitae, SCV002228646.2). Another missense variant c.1127G>C (p.Cys376Ser) in the same codon is classified as pathogenic for autosomal dominant alpha-actinopathy (PM5, PMIDs:25890230, 19562689). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024).