ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2063A>G (p.Tyr688Cys) (rs145248415)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766297 SCV000566773 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing The c.2063A>G variant in the ACTN2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.2063A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico prediction models predict that c.2063A>G may create a cryptic splice donor site upstream of the natural splice donor site in intron 17. However, in the absence of RNA/functional studies, the actual effect of c.2063A>G in this individual is unknown. If c.2063A>G does not alter splicing, then it will result in the Y688C missense change. The Y688C 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 across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.2063A>G as a variant of uncertain significance.
Invitae RCV000704626 SCV000833582 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 688 of the ACTN2 protein (p.Tyr688Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 162739). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150150 SCV000197032 uncertain significance not specified 2013-07-03 criteria provided, single submitter clinical testing The Tyr688Cys variant in ACTN2 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14524 8415). Computational analyses (biochemical amino acid properties, conservation, splice site tools, AlignGVGD, PolyPhen2, and SIFT) suggest that the Tyr688Cys v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the Tyr688Cys variant.

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