NM_001103.3(ACTN2):c.1748A>G (p.Glu583Gly) AND not specified

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 24, 2015
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:: RCV000183264.2

Allele description

NM_001103.3(ACTN2):c.1748A>G (p.Glu583Gly)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_001103.3(ACTN2):c.1748A>G (p.Glu583Gly)

Other names:

p.E583G:GAG>GGG

HGVS:

NC_000001.11:g.236751561A>G
NG_009081.1:g.70092A>G
NM_001103.3:c.1748A>G
NM_001278343.1:c.1748A>G
NP_001094.1:p.Glu583Gly
NP_001265272.1:p.Glu583Gly
NC_000001.10:g.236914861A>G
NM_001103.2:c.1748A>G

Protein change:

E583G

Links:

dbSNP: rs200631005

GMAF:

0.0002(G), 200631005

NCBI 1000 Genomes Browser:

rs200631005

Allele Frequency:

0.00088(G)

Molecular consequence:

NM_001103.3:c.1748A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235690	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Sep 24, 2015)	germline	clinical testing	Citation Link,
SCV000280040	Stanford Center for Inherited Cardiovascular Disease,Stanford University	no assertion criteria provided	Uncertain significance (Apr 8, 2015)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235690

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Sep 24, 2015)

germline

clinical testing

Citation Link,

SCV000280040

Stanford Center for Inherited Cardiovascular Disease,Stanford University

no assertion criteria provided

Uncertain significance
(Apr 8, 2015)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000235690.5

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

Description

A variant of unknown significance has been identified in the ACTN2 gene. The E583G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E583G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. A mutation in the same residue (E583A) has been reported in HGMD in association with HCM (Stenson P et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, E583G was reported in 1/694 (0.1%) alleles from individuals of ad Mixed American ancestry (McVean et al., 2012)Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant

#	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

From Stanford Center for Inherited Cardiovascular Disease,Stanford University, SCV000280040.1

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

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we consider this a variant of unknown significance-likely benign. The variant has not previously been reported in association with disease. However, a variant at the same codon has been associated with hypertrophic cardiomyopathy (HCM): p.Glu583Ala, supporting the functional importance of this region of the protein (Chiu et al. 2010). No segregation analysis is available. This is a non-conservative amino acid substitution of a negatively charged glutamic acid with a nonpolar glycine (which has the smallest of any amino acid side-chain). The glutamic acid at codon 583 is not conserved across 9 vertebrate species, differing in zebrafish and lamprey. In silico analysis with PolyPhen-2 predicts the variant to be “benign” with a score of 0.414. No variants have been reported at nearby codons in HGMD. In total the variant has been seen in 1 of ~7500 individuals from publicly available population datasets. p.Glu583Gly was found in one individual of Mexican ancestry in 1000 genomes, and it is listed in dbSNP as rs200631005. The variant is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Additionally, as of 23 September 2015. UPDATE 9/23/2015: ExAC reports that 106 out of 5786 Latino individuals in the database have this variant. This is almost 2% of Latinos, and so we have reclassified it as a VUS-probably benign (but we are leaning toward benign).

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

Last Updated: Feb 22, 2017

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