Variant: NM_001100.4(ACTA1):c.435C>A (p.Tyr145Ter)

CA1442883

280863 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 81b0aa59-8d57-4021-8615-6f4a697a1da2

Approved on: 2024-08-07

Published on: 2024-12-19

HGVS expressions

NM_001100.4:c.435C>A
NM_001100.4(ACTA1):c.435C>A (p.Tyr145Ter)
NC_000001.11:g.229432575G>T
CM000663.2:g.229432575G>T
NC_000001.10:g.229568322G>T
CM000663.1:g.229568322G>T
NC_000001.9:g.227634945G>T
NG_006672.1:g.6522C>A
ENST00000366683.4:c.435C>A
ENST00000684723.1:c.300C>A
ENST00000366683.3:c.435C>A
ENST00000366684.7:c.435C>A
NM_001100.3:c.435C>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PVS1

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 c.435C>A (p.Tyr145Ter) variant in ACTA1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/7 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism for autosomal recessive nemaline myopathy (PVS1). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.000002480 (4/1179732 alleles) in the European (non-Finnish) population (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_P. (Congenital Myopathies VCEP specifications version 1; 08/07/2024)

Met criteria codes

• PM2_Supporting: The highest population filtering allele frequency in gnomAD v4.1.0 is 0.000002480 (4/1179732 alleles) in the European (non-Finnish) population (PM2_Supporting).
• PVS1: The c.435C>A (p.Tyr145Ter) variant in ACTA1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/7 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism for autosomal recessive nemaline myopathy (PVS1).