Variant: NM_001100.4(ACTA1):c.172G>A (p.Asp58Asn)

CA345150874

427190 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: c6230021-44c3-448a-9d24-ff554c173be1

Approved on: 2024-08-27

Published on: 2025-01-03

HGVS expressions

NM_001100.4:c.172G>A
NM_001100.4(ACTA1):c.172G>A (p.Asp58Asn)
NC_000001.11:g.229432838C>T
CM000663.2:g.229432838C>T
NC_000001.10:g.229568585C>T
CM000663.1:g.229568585C>T
NC_000001.9:g.227635208C>T
NG_006672.1:g.6259G>A
ENST00000366683.4:c.172G>A
ENST00000684723.1:c.37G>A
ENST00000366683.3:c.172G>A
ENST00000366684.7:c.172G>A
NM_001100.3:c.172G>A

Likely Pathogenic

• Met criteria codes: PS2 PP3 PP2 PM2_Supporting

• Not Met criteria codes: PS4

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.172G>A variant in ACTA 1 is a missense variant predicted to cause a substitution of aspartic acid by asparagine at amino acid position 58. 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 was observed to occur de novo in a proband with congenital hypotonia, muscle weakness, failure to thrive, poor feeding, developmental delay and normal creatine kinase levels (PS2, SCV000934090.3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024).

Met criteria codes

• PS2: This variant was observed to occur de novo in a proband with congenital hypotonia, muscle weakness, failure to thrive, poor feeding, developmental delay and normal creatine kinase levels (PS2, Invitae internal data, SCV000934090.3).
• PP3: The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.75
• PP2: ACTA1, in which the variant was identified, is defined by the ClinGen CM 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). gnomAD Z score = 6.09
• PM2_Supporting: This variant is absent from gnomAD v4.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant was observed to occur de novo in a proband with congenital hypotonia, muscle weakness, failure to thrive, poor feeding, developmental delay and normal creatine kinase levels (SCV000934090.3).