ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2386C>T (p.Arg796Cys) (rs397516574)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036900 SCV000060555 uncertain significance not specified 2011-10-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg796Cys v ariant has not been reported or previously identified by our laboratory out of > 350 Caucasian probands (>700 chromosomes) tested. Arginine (Arg) at position 796 is highly conserved across evolutionarily distant species, increasing the likel ihood that a change would not be tolerated. In addition, three computational mod els (AlignGVGD, Polyphen2, SIFT) predict this change to be deleterious, though t he accuracy of these tools is unknown. Although this data suggests that the Arg 796Cys variant may be pathogenic, additional information is required to assess t he clinical significance of this variant.
GeneDx RCV000766826 SCV000618569 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The R796C variant has previously been reported in one individual with HCM (Walsh et al., 2017). In addition, R796C has been identified independently of additional cardiogenetic variants in one other individual referred for HCM genetic testing at GeneDx. Thus far, no informative segregation data are available for the published case or the one observed at GeneDx. The R796C variant is observed in 5/126724 (0.004%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The R796C 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. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000638634 SCV000760171 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 796 of the ACTN2 protein (p.Arg796Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397516574, ExAC 0.001%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43928). 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. 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.
Center for Human Genetics,University of Leuven RCV000768498 SCV000886803 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing

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