NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys) AND Actin accumulation myopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 17, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000228987.5

Allele description [Variation Report for NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys)]

NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys)

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.923A>G (p.Tyr308Cys)

HGVS:

NC_000001.11:g.229431788T>C
NG_006672.1:g.7309A>G
NM_001100.4:c.923A>GMANE SELECT
NP_001091.1:p.Tyr308Cys
NP_001091.1:p.Tyr308Cys
LRG_429t1:c.923A>G
LRG_429:g.7309A>G
LRG_429p1:p.Tyr308Cys
NC_000001.10:g.229567535T>C
NM_001100.3:c.923A>G

Protein change:

Y308C

Links:

dbSNP: rs878854374

NCBI 1000 Genomes Browser:

rs878854374

Molecular consequence:

NM_001100.4:c.923A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Actin accumulation myopathy (CMYP2A)
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
SCV000265785	Center for Genetic Medicine Research, Children's National Medical Center	criteria provided, single submitter (Punetha et al. (J Neuromuscul Dis. 2016))	Likely pathogenic (Dec 1, 2015)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV003524159	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25987458, 27854218, 32222963, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000265785

Center for Genetic Medicine Research, Children's National Medical Center

criteria provided, single submitter

(Punetha et al. (J Neuromuscul Dis. 2016))

Likely pathogenic
(Dec 1, 2015)

unknown

research

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

SCV003524159

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 17, 2023)

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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

Dai Y, Wei X, Zhao Y, Ren H, Lan Z, Yang Y, Chen L, Cui L.

Neuromuscul Disord. 2015 Aug;25(8):617-24. doi: 10.1016/j.nmd.2015.03.002. Epub 2015 Mar 17.

PubMed [citation]

PMID:: 25987458

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

Punetha J, Kesari A, Uapinyoying P, Giri M, Clarke NF, Waddell LB, North KN, Ghaoui R, O'Grady GL, Oates EC, Sandaradura SA, Bönnemann CG, Donkervoort S, Plotz PH, Smith EC, Tesi-Rocha C, Bertorini TE, Tarnopolsky MA, Reitter B, Hausmanowa-Petrusewicz I, Hoffman EP.

J Neuromuscul Dis. 2016 May 27;3(2):209-225.

PubMed [citation]

PMID:: 27854218

See all PubMed Citations (4)

Details of each submission

From Center for Genetic Medicine Research, Children's National Medical Center, SCV000265785.2

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

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

From Invitae, SCV003524159.2

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 308 of the ACTA1 protein (p.Tyr308Cys). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt ACTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 224672). This missense change has been observed in individual(s) with clinical features of autosomal dominant ACTA1-related conditions (PMID: 25987458, 27854218, 32222963).

#	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: Mar 16, 2024

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