Variant: NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)

CA341499

18291 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 0700c61d-d15f-4e6d-b5eb-4aacac32eeb5

Approved on: 2024-10-25

Published on: 2025-04-02

HGVS expressions

NM_001100.4:c.1000C>T
NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)
NC_000001.11:g.229431633G>A
CM000663.2:g.229431633G>A
NC_000001.10:g.229567380G>A
CM000663.1:g.229567380G>A
NC_000001.9:g.227634003G>A
NG_006672.1:g.7464C>T
ENST00000366683.4:c.991-69C>T
ENST00000684723.1:c.865C>T
ENST00000366683.3:c.631C>T
ENST00000366684.7:c.1000C>T
NM_001100.3:c.1000C>T

Pathogenic

• Met criteria codes: PM2_Supporting PS3 PM5 PP4 PP3 PP2

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 c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). 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 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). 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: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Coverage of the gene in the region this variant is found is adequate.
• PS3: Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). Code is applied at the strong level due to evidence in two different cell types and specificity of evidence.
• PM5: 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5).
• PP4: One patient with this variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data).
• PP3: The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (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 (PP2). ACTA1 has a Z-score of 6.09 for missense variants.