Variant: NM_001100.4(ACTA1):c.541del (p.Asp181fs)

CA1442845

420100 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: b0b43b29-0998-4f68-992c-a07ff5a3d9a6

Approved on: 2024-08-07

Published on: 2024-12-19

HGVS expressions

NM_001100.4:c.541del
NM_001100.4(ACTA1):c.541del (p.Asp181fs)
NC_000001.11:g.229432346del
CM000663.2:g.229432346del
NC_000001.10:g.229568093del
CM000663.1:g.229568093del
NC_000001.9:g.227634716del
NG_006672.1:g.6752del
ENST00000366683.4:c.541del
ENST00000684723.1:c.406del
ENST00000366683.3:c.479+62del
ENST00000366684.7:c.541del
NM_001100.3:c.541del

Pathogenic

• Met criteria codes: PVS1 PS3_Supporting PP4_Moderate PM3

• Not Met criteria codes: BA1 BS1 PM2

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 1.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001100.4:c.541del (p.Asp181fs) variant in ACTA1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 4/7 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population filtering allele frequency in gnomAD v4.1 is 0.0002402 (29/91056 alleles) in the South Asian population (this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant). This variant has been detected in 6 individuals with nemaline myopathy. All of these individuals were homozygous for the variant (PMID: 17187373, GeneDx, SCV000568673.4) (PM3). Multiple patients with this variant displayed zebra bodies, which is highly specific for nemaline myopathy (PP4, PMID: 17187373). Western blot analysis of the muscle biopsy in one of the patients showed complete absence of α-skeletal muscle actin, whereas they had high levels of α-cardiac actin when compared with control subjects indicating that this variant impacts protein expression (PMID: 17187373) (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM3, PS3_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024).

Met criteria codes

• PVS1: The c.541del (p.Asp181fs) variant in ACTA1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 4/7 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PS3_Supporting: Western blot analysis of the muscle biopsy in Patient 3 showed complete absence of α-skeletal muscle actin, whereas they had high levels of α-cardiac actin when compared with control subjects indicating that this variant impacts protein function (PMID: 17187373)(PS3_Supporting).
• PP4_Moderate: Multiple patients with this variant displayed zebra bodies, which is highly specific for nemaline myopathy (PP4, PMID: 17187373).
• PM3: This variant has been detected in 6 individuals with nemaline myopathy. All individuals were homozygous for the variant (PM3, PMID: 17187373, GeneDx, SCV000568673.4). Heterozygous parents were unaffected.

Not Met criteria codes

• BA1: The highest population filtering allele frequency in gnomAD v4.1 is 0.0002402 (29/91056 alleles) in the South Asian population (BA1 is not met as this variant is excluded).
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline