Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001100.4(ACTA1):c.37G>A (p.Asp13Asn)

CA345151718

642798 (ClinVar)

Gene: ACTA1 (HGNC:58)

Condition: alpha-actinopathy (MONDO:0100084)

Inheritance Mode: Autosomal dominant inheritance

UUID: 81bf4e47-2384-4391-8fc9-1fd751d9fa35

Approved on: 2024-12-09

Published on: 2025-06-26

HGVS expressions

NM_001100.4(ACTA1):c.37G>A (p.Asp13Asn)

NM_001100.4:c.37G>A

NC_000001.11:g.229433079C>T

CM000663.2:g.229433079C>T

NC_000001.10:g.229568826C>T

CM000663.1:g.229568826C>T

NC_000001.9:g.227635449C>T

NG_006672.1:g.6018G>A

ENST00000366683.4:c.37G>A

ENST00000684723.1:c.-6-199G>A

ENST00000366683.3:c.37G>A

ENST00000366684.7:c.37G>A

NM_001100.3:c.37G>A

Likely Pathogenic

PS2 PP3 PP2 PM2_Supporting

BP5 BP7 BP2 BP3 BP4 BP1 PS4 PS3 PS1 PP4 PP1 PM3 PM1 PM4 PM5 PM6 BA1 PVS1 BS4 BS3 BS1 BS2

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001100.4 c.37G>A (p.Asp13Asn) variant in ACTA1 is a missense variant predicted to cause a substitution of aspartic acid by asparagine at amino acid 13. ACTA1 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 0.763, which is above the threshold for predicting a damaging effect on ACTA1 variants (PP3). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been identified as de novo by trio analysis in one proband with clinical features of congenital myopathy (ARUP Laboratories; SCV001157803.1) (PS2). 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 Myopathy VCEP: PP2, PP3, PM2_Supporting, PS2; ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 12/9/2024

PS2

According to ARUP, their patient with the variant was found to have the variant de novo by trio analysis

PP3

Multiple lines of computational evidence support a deleterious effect with on the gene or gene product including a REVEL score >0.7 as specified in VCEP's PP3 criteria

PP2

The c.37G>A (p.Asp13Asn) variant is a missense variant in ACTA1 which is constrained for missense variants.

PM2_Supporting

Absent from gnomAD, ExAC, and 1000 Genomes

BP5

In PMID: 19562689 patient with variant was diagnosed with NMR however there could be overlap with other congenital myopathy phenotypes, GeneDx reported that the proband was negative for a NEB exon 55 deletion. ARUP reported their proband had distal arthrogryposis, central apnea, undescended testes, metabolic acidosis, central hypotonia, wrist and finger contractures, club foot, diminished reflexes, hypertonia, and spasticity.

BP7

Missense variant is non-synonymous

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP3

Missense variant

BP4

Multiple lines of computational evidence support a deleterious effect

BP1

Missense variants in ACTA1 are associated with pathogenicity therefore BP1 is not applicable to variants in ACTA1

PS4

Only one patient reported by ARUP lab was scorable. PMID: 19562689 discusses one proband with NMR without additional phenotype or inheritance information, and was not scored.

PS3

No functional studies of variant available.

PS1

No pathogenic variants in the same codon causing the same amino acid change has been identified

PP4

Patient phenotype as reported by ARUP as the following: "infant had distal arthrogryposis, central apnea, undescended testes, metabolic acidosis, central hypotonia, wrist and finger contractures, club foot, diminished reflexes, hypertonia and spasticity." In PMID: 19562689 patient with variant was diagnosed with NMR.

PP1

Segregation data not available

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

There are no mutational hot spots in ACTA1 per VCEP guidance and PMID: 19562689

PM4

Missense variant

PM5

NM_001100.4(ACTA1):c.39C>A (p.Asp13Glu) has been interpreted as pathogenic by LabCorp in ClinVar, yet VUS by GeneDx and there does not seem to be sufficient evidence in the literature to interpret this variant as pathogenic by ClinGen standards therefore, I do not feel PM5 can be invoked in this case.

PM6

Paternity and maternity confirmed

BA1

Absent from gnomAD, ExAC, and 1000 Genomes

PVS1

Missense variant not affecting canonical splice sites

BS4

Segregation data not available

BS3

No functional studies of variant available.

BS1

Absent from gnomAD, ExAC, and 1000 Genomes

BS2

Absent from population databases and dominant ACTA1 mutations are not fully penetrant per PMID: 19562689

Curation History

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