NM_001103.4(ACTN2):c.2138C>T (p.Thr713Met) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 28, 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:: RCV000686268.6

Allele description [Variation Report for NM_001103.4(ACTN2):c.2138C>T (p.Thr713Met)]

NM_001103.4(ACTN2):c.2138C>T (p.Thr713Met)

Gene:

ACTN2:actinin alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_001103.4(ACTN2):c.2138C>T (p.Thr713Met)

HGVS:

NC_000001.11:g.236755182C>T
NG_009081.2:g.96042C>T
NM_001103.2:c.2138C>T
NM_001103.4:c.2138C>TMANE SELECT
NM_001278343.2:c.2138C>T
NM_001278344.2:c.1514C>T
NP_001094.1:p.Thr713Met
NP_001094.1:p.Thr713Met
NP_001265272.1:p.Thr713Met
NP_001265273.1:p.Thr505Met
LRG_436t1:c.2138C>T
LRG_436:g.96042C>T
LRG_436p1:p.Thr713Met
NC_000001.10:g.236918482C>T
NG_009081.1:g.73713C>T
NM_001103.3:c.2138C>T

Protein change:

T505M

Links:

dbSNP: rs764538888

NCBI 1000 Genomes Browser:

rs764538888

Molecular consequence:

NM_001103.4:c.2138C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278343.2:c.2138C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278344.2:c.1514C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1AA (CMD1AA)
Synonyms:: CARDIOMYOPATHY, DILATED, 1AA, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION
Identifiers:: MONDO: MONDO:0012808; MedGen: C2677338; Orphanet: 154; OMIM: 612158

Name:: Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:: Hereditary ventricular hypertrophy; Idiopathic hypertrophic subaortic stenosis
Identifiers:: MONDO: MONDO:0024573; MeSH: D024741; MedGen: C0949658; OMIM: PS192600

Recent activity

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serpin B12 isoform 2 [Homo sapiens]
serpin B12 isoform 2 [Homo sapiens]
gi|17998551|ref|NP_536722.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000813779	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813779

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 28, 2022)

germline

clinical testing

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

Citations

PubMed

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000813779.3

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 713 of the ACTN2 protein (p.Thr713Met). This variant is present in population databases (rs764538888, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 566457). 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 ACTN2 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: Sep 29, 2024

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