NM_001103.4(ACTN2):c.2575G>A (p.Ala859Thr) AND Intrinsic cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 11, 2021
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:: RCV001788846.3

Allele description [Variation Report for NM_001103.4(ACTN2):c.2575G>A (p.Ala859Thr)]

NM_001103.4(ACTN2):c.2575G>A (p.Ala859Thr)

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.2575G>A (p.Ala859Thr)

HGVS:

NC_000001.11:g.236762509G>A
NG_009081.2:g.103369G>A
NM_001103.4:c.2575G>AMANE SELECT
NM_001278343.2:c.2575G>A
NM_001278344.2:c.1951G>A
NP_001094.1:p.Ala859Thr
NP_001265272.1:p.Ala859Thr
NP_001265273.1:p.Ala651Thr
LRG_436t1:c.2575G>A
LRG_436:g.103369G>A
LRG_436p1:p.Ala859Thr
NC_000001.10:g.236925809G>A
NG_009081.1:g.81040G>A

Protein change:

A651T

Links:

dbSNP: rs2102953709

NCBI 1000 Genomes Browser:

rs2102953709

Molecular consequence:

NM_001103.4:c.2575G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278343.2:c.2575G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278344.2:c.1951G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intrinsic cardiomyopathy
Identifiers:: MONDO: MONDO:0000591; MedGen: CN305117

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SLC35G1 [Gorilla gorilla gorilla]
SLC35G1 [Gorilla gorilla gorilla]
Gene ID:101149078

Gene
Pterocladiella capillacea voucher AST643746 cytochrome c oxidase subunit I gene,...
Pterocladiella capillacea voucher AST643746 cytochrome c oxidase subunit I gene, partial cds; mitochondrial
gi|1798176489|gb|MK987033.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002029236	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 11, 2021)	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

SCV002029236

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 11, 2021)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002029236.3

#	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 in ACTN2 is predicted to replace alanine with threonine at codon 859 (p.(Ala859Thr)). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in a helical region (UniProt). There is a small physicochemical difference between alanine and threonine. This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with ACTN2-related disease. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.

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

Last Updated: Apr 15, 2024

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