ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1748A>G (p.Glu583Gly) (rs200631005)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183264 SCV000235690 likely benign not specified 2018-02-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000234704 SCV000285862 benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000241991 SCV000320655 likely benign Cardiovascular phenotype 2018-08-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification
Mendelics RCV000986573 SCV001135593 likely benign Dilated cardiomyopathy 1AA 2019-05-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183264 SCV000280040 uncertain significance not specified 2015-04-08 no assertion criteria provided clinical testing 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).

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