NM_001100.4(ACTA1):c.587C>T (p.Thr196Ile) AND Actin accumulation myopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 26, 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:: RCV001988135.4

Allele description [Variation Report for NM_001100.4(ACTA1):c.587C>T (p.Thr196Ile)]

NM_001100.4(ACTA1):c.587C>T (p.Thr196Ile)

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.587C>T (p.Thr196Ile)

HGVS:

NC_000001.11:g.229432299G>A
NG_006672.1:g.6798C>T
NM_001100.3:c.587C>T
NM_001100.4:c.587C>TMANE SELECT
NP_001091.1:p.Thr196Ile
LRG_429t1:c.587C>T
LRG_429:g.6798C>T
NC_000001.10:g.229568046G>A

Protein change:

T196I

Links:

dbSNP: rs2102735869

NCBI 1000 Genomes Browser:

rs2102735869

Molecular consequence:

NM_001100.4:c.587C>T - 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
SCV002220856	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31321302, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002220856

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 26, 2022)

germline

clinical testing

PubMed (2)
[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

Congenital myopathies in the adult neuromuscular clinic: Diagnostic challenges and pitfalls.

Nicolau S, Liewluck T, Tracy JA, Laughlin RS, Milone M.

Neurol Genet. 2019 Aug;5(4):e341. doi: 10.1212/NXG.0000000000000341.

PubMed [citation]

PMID:: 31321302
PMCID:: PMC6563518

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002220856.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 196 of the ACTA1 protein (p.Thr196Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital myopathy (PMID: 31321302). ClinVar contains an entry for this variant (Variation ID: 1447156). 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. 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.

#	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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