Variant: NM_001100.4(ACTA1):c.442G>A (p.Gly148Ser)

CA221485

93549 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: a695743f-28f5-4e59-ad87-db52db959e09

Approved on: 2025-03-10

Published on: 2025-04-01

HGVS expressions

NM_001100.4:c.442G>A
NM_001100.4(ACTA1):c.442G>A (p.Gly148Ser)
NC_000001.11:g.229432568C>T
CM000663.2:g.229432568C>T
NC_000001.10:g.229568315C>T
CM000663.1:g.229568315C>T
NC_000001.9:g.227634938C>T
NG_006672.1:g.6529G>A
ENST00000366683.4:c.442G>A
ENST00000684723.1:c.307G>A
ENST00000366683.3:c.442G>A
ENST00000366684.7:c.442G>A
NM_001100.3:c.442G>A

Likely Pathogenic

• Met criteria codes: PS4_Supporting PM2_Supporting PP3 PP2 PM6

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 2.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The variant NM_001100.4:c.442G>A in ACTA1 is a missense variant predicted to cause substitution of glycine by serine at amino acid 148 (p.Gly148Ser). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.935, which is above the threshold necessary to apply 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). Two different missense variants, p.Gly148Arg and p.Gly148Val (Variation IDs: 280732 and 2582809), in the same codon have been classified as likely pathogenic for alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5 applied to p.Gly148Val). This variant has been reported in 3 probands with alpha-actinopathy, and one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PS4_Supporting, PM6; PMIDs: 19562689, 32222963. SCV000680134.1). In summary, this variant meets the criteria to be classified as likely pathogenic for AD alpha-actinopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 2.0.0): PM2_Supporting, PP3, PP2, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 3/10/2025).

Met criteria codes

• PS4_Supporting: This variant has been reported in 3 probands with alpha-actinopathy, meeting PS4_Supporting (PMID: 32222963, PMID: 19562689, Institute of Human Genetics Munich)
• PM2_Supporting: Variant absent from GnomAD v4.1.0
• PP3: The REVEL computational prediction analysis tool produced a score of 0.935, which is above the threshold necessary to apply PP3
• PP2: 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.
• PM6: One proband was reported as a de novo occurrence with unconfirmed parental relationship (Institute of Human Genetics Munich)