NM_001100.4(ACTA1):c.1075A>G (p.Ile359Val) AND Actin accumulation myopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 19, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002833792.2

Allele description [Variation Report for NM_001100.4(ACTA1):c.1075A>G (p.Ile359Val)]

NM_001100.4(ACTA1):c.1075A>G (p.Ile359Val)

Gene:

ACTA1:actin alpha 1, skeletal muscle [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q42.13

Genomic location:

Preferred name:

NM_001100.4(ACTA1):c.1075A>G (p.Ile359Val)

HGVS:

NC_000001.11:g.229431558T>C
NG_006672.1:g.7539A>G
NG_093759.1:g.563T>C
NM_001100.4:c.1075A>GMANE SELECT
NP_001091.1:p.Ile359Val
NP_001091.1:p.Ile359Val
LRG_429t1:c.1075A>G
LRG_429:g.7539A>G
LRG_429p1:p.Ile359Val
NC_000001.10:g.229567305T>C
NM_001100.3:c.1075A>G

Protein change:

I359V

Molecular consequence:

NM_001100.4:c.1075A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Actin accumulation myopathy (CMYO2A)
Synonyms:: Nemaline myopathy caused by mutation in the alpha-actin gene; CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT; Myopathy, actin, congenital, with cores; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008070; MedGen: C3711389; OMIM: 161800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003216868	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 19, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11333380, 15198992, 15226407, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003216868

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 19, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.

Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, Durling HJ, Roddick LG, Wilkinson I, Kornberg AJ, Collins KJ, Wallace G, Gunning P, Hardeman EC, Laing NG, North KN.

Am J Hum Genet. 2001 Jun;68(6):1333-43. Epub 2001 Apr 27.

PubMed [citation]

PMID:: 11333380
PMCID:: PMC1226120

Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms.

Ilkovski B, Nowak KJ, Domazetovska A, Maxwell AL, Clement S, Davies KE, Laing NG, North KN, Cooper ST.

Hum Mol Genet. 2004 Aug 15;13(16):1727-43. Epub 2004 Jun 15.

PubMed [citation]

PMID:: 15198992

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV003216868.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant disrupts the p.Ile359 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11333380, 15198992, 15226407). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTA1 protein function. This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 359 of the ACTA1 protein (p.Ile359Val).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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