NM_001103.4(ACTN2):c.1473C>G (p.Asp491Glu) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 24, 2023
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:: RCV003802788.1

Allele description

NM_001103.4(ACTN2):c.1473C>G (p.Asp491Glu)

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.1473C>G (p.Asp491Glu)

HGVS:

NC_000001.11:g.236747733C>G
NG_009081.2:g.88593C>G
NM_001103.4:c.1473C>GMANE SELECT
NM_001278343.2:c.1473C>G
NM_001278344.2:c.849C>G
NM_001412150.1:c.723C>G
NP_001094.1:p.Asp491Glu
NP_001265272.1:p.Asp491Glu
NP_001265273.1:p.Asp283Glu
NP_001399079.1:p.Asp241Glu
LRG_436t1:c.1473C>G
LRG_436:g.88593C>G
LRG_436p1:p.Asp491Glu
NC_000001.10:g.236911033C>G
NR_184402.1:n.1845C>G

Protein change:

D241E

Molecular consequence:

NM_001103.4:c.1473C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001278343.2:c.1473C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001278344.2:c.849C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001412150.1:c.723C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_184402.1:n.1845C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

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FAD-binding oxidoreductase [Agrobacterium tumefaciens]
FAD-binding oxidoreductase [Agrobacterium tumefaciens]
gi|2685278033|ref|WP_333723282.1|

Protein
Chain N, Ragulator complex protein LAMTOR2
Chain N, Ragulator complex protein LAMTOR2
gi|2367144301|pdb|7UXC|N

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004591695	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 24, 2023)	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

SCV004591695

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 24, 2023)

germline

clinical testing

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

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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 Invitae, SCV004591695.1

#	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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 491 of the ACTN2 protein (p.Asp491Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. 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 ACTN2 protein function with a negative predictive value of 80%. 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: Mar 5, 2024

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