ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.727G>A (p.Glu243Lys) (rs794728712)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182665 SCV000235044 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing The E243K variant in the RYR2 gene has been reported in one individual with definitive CPVT and one individual with either strong or possible CPVT (Hayashi et al., 2009; Medeiros-Domingo et al., 2009). The E243K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E243K 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, and this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The E243K variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense mutations occur (Medeiros-Domingo et al., 2009). Although this region is not a channel functional domain and there are no nearby definitively pathogenic variants, a handful of individuals identified by GeneDx to harbor this variant reported syncope and/or sudden cardiac arrest and at least one individual had syncope with exertion, suggesting that this variant may be pathogenic, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Furthermore, no individual carrying this variant reported a clearly strong clinical diagnosis of CPVT or ARVC, and some individuals harbored additional cardiogenetic variants of uncertain significance. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Ambry Genetics RCV000618334 SCV000737687 uncertain significance Cardiovascular phenotype 2016-09-02 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000691663 SCV000819451 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-06-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 243 of the RYR2 protein (p.Glu243Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) or RYR2-related clinical features (PMID: 19398665, 19926015, 29453246). ClinVar contains an entry for this variant (Variation ID: 201200). 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.

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