ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2108A>T (p.Gln703Leu) (rs370862426)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621090 SCV000736020 uncertain significance Cardiovascular phenotype 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000549504 SCV000636950 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with leucine at codon 703 of the ACTN2 protein (p.Gln703Leu). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is present in population databases (rs370862426, ExAC 0.05%) but has not been reported in the literature in individuals with a ACTN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000615469 SCV000731589 uncertain significance not specified 2017-03-30 criteria provided, single submitter clinical testing The p.Gln703Leu variant in ACTN2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/8644 East Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370862426). Computational prediction tools and conservation analysis suggest t hat the p.Gln703Leu variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, the clinical signif icance of the p.Gln703Leu variant is uncertain.

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