Variant: NM_001100.4(ACTA1):c.442G>C (p.Gly148Arg)

Version: 1.0
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CA10602749

280732 (ClinVar)

Gene: ACTA1 (HGNC:58)

Condition: alpha-actinopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: bf278676-8839-418d-8172-5dfe7e2b7758

Approved on: 2025-03-10

Published on: 2025-04-01

HGVS expressions

NM_001100.4:c.442G>C
NM_001100.4(ACTA1):c.442G>C (p.Gly148Arg)
NC_000001.11:g.229432568C>G
CM000663.2:g.229432568C>G
NC_000001.10:g.229568315C>G
CM000663.1:g.229568315C>G
NC_000001.9:g.227634938C>G
NG_006672.1:g.6529G>C
ENST00000366683.4:c.442G>C
ENST00000684723.1:c.307G>C
ENST00000366683.3:c.442G>C
ENST00000366684.7:c.442G>C
NM_001100.3:c.442G>C

Likely Pathogenic

• Met criteria codes: PS2 PP3 PP2 PS4_Supporting PM2_Supporting

• Not Met criteria codes: PS3 PP4 PP1 PM3 PM1 PM4 PM6 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP1 BP3 BP5 BP7

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>C in ACTA1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 148 (p.Gly148Arg). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.979, 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.Gly148Ser and p.Gly148Val (Variation IDs: 1364817 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 2 probands with alpha-actinopathy, and one of these probands had a de novo occurrence of the variant with parental relationships confirmed (PS4_Supporting, PS2; PMID: 33820833. SCV000330673.6). 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, PS2 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 3/10/2025).

Met criteria codes

• PS2: GeneDx reported this variant as de novo via trio testing and sequencing data was suggestive of mosaicism as the variant allele was underrepresented.
• PP3: The REVEL computational prediction analysis tool produced a score of 0.935, which is above the threshold necessary to apply PP3
• PP2: Although the variant is not documented in the literature, other variants resulting in different amino acid changes in the same codon have been described as autosomal dominant as are 90% of ACTA1 variants so this variant is assumed to potentially be autosomal dominant and thus be constrained for missense variants.
• PS4_Supporting: This variant has been reported in 2 probands with alpha-actinopathy (PMID: 33820833, GeneDx internal data)
• PM2_Supporting: Variant is absent from controls

Not Met criteria codes

• PS3: No functional data
• PP4: Probands either did not have muscle biopsies performed or did not show characteristic pathology.
• PP1: Segregation data not available
• PM3: This is most likely an autosomal dominant variant but no patients in the literature have been observed.
• PM1: ACTA1 is not applicable for PM1
• PM4: Not applicable for missense variant
• PM6: Maternity and paternity confirmed via trio analysis
• PVS1: Not applicable for missense variant
• BA1: Variant is absent from controls
• BS2: No available controls had the variant
• BS4: Segregation data not available
• BS3: No functional data
• BS1: Variant is absent from controls
• BP2: This is most likely an autosomal dominant variant but no patients in the literature have been observed.
• BP1: Missense variants are a known mechanism of disease
• BP3: Not applicable for missense variant
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: Not applicable for missense variant