NM_001100.4(ACTA1):c.541del (p.Asp181fs) AND Actin accumulation myopathy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001384035.9

Allele description [Variation Report for NM_001100.4(ACTA1):c.541del (p.Asp181fs)]

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

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1q42.13

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000001.11:g.229432346del
NG_006672.1:g.6752del
NG_093760.1:g.731del
NM_001100.4:c.541delMANE SELECT
NP_001091.1:p.Asp181Thrfs
NP_001091.1:p.Asp181fs
NP_001091.1:p.Asp181fs
LRG_429t1:c.541del
LRG_429:g.6752del
LRG_429p1:p.Asp181fs
NC_000001.10:g.229568092del
NC_000001.10:g.229568093del
NM_001100.3:c.540delG
NM_001100.3:c.541del
NM_001100.3:c.541delG

Protein change:

D181fs

Links:

OMIM: 102610.0022; dbSNP: rs759242559

NCBI 1000 Genomes Browser:

rs759242559

Molecular consequence:

NM_001100.4:c.541del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001583399	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19562689, 17187373, 28492532
SCV003761240	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 25, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001583399

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003761240

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 25, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

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, curation

Citations

PubMed

Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1).

Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S, Winder TL, Lochmüller H, Graziano C, Mitrani-Rosenbaum S, Twomey D, Sparrow JC, Beggs AH, Nowak KJ.

Hum Mutat. 2009 Sep;30(9):1267-77. doi: 10.1002/humu.21059.

PubMed [citation]

PMID:: 19562689
PMCID:: PMC2784950

Nemaline myopathy caused by absence of alpha-skeletal muscle actin.

Nowak KJ, Sewry CA, Navarro C, Squier W, Reina C, Ricoy JR, Jayawant SS, Childs AM, Dobbie JA, Appleton RE, Mountford RC, Walker KR, Clement S, Barois A, Muntoni F, Romero NB, Laing NG.

Ann Neurol. 2007 Feb;61(2):175-84.

PubMed [citation]

PMID:: 17187373

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001583399.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Asp181Thrfs*11) in the ACTA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACTA1 are known to be pathogenic (PMID: 19562689). This variant is present in population databases (rs759242559, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myopathy (PMID: 17187373). ClinVar contains an entry for this variant (Variation ID: 420100). For these reasons, this variant has been classified as Pathogenic.

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761240.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The homozygous p.Asp181ThrfsTer11 variant in ACTA1 was identified by our study in one individual with nemaline myopathy. The p.Asp181ThrfsTer11 variant in ACTA1 has been previously reported in four individuals with autosomal recessive nemaline myopathy (PMID: 17187373) but has been identified in 0.03% (10/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs759242559). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these four affected individuals previously reported, all (four) were homozygotes, which increases the likelihood that the p.Asp181ThrfsTer11 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID:420100) and has been interpreted as pathogenic by GeneDx, Invitae, and PerkinElmer Genomics. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 181 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ACTA1 gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015).

#	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: Oct 13, 2024

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