ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4912T>A (p.Ser1638Thr) (rs794728739)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618600 SCV000734885 uncertain significance Cardiovascular phenotype 2016-06-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768770 SCV000900140 uncertain significance Cardiomyopathy 2016-11-16 criteria provided, single submitter clinical testing
GeneDx RCV000182729 SCV000235113 uncertain significance not provided 2016-07-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The S1638T variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.This variant has been identified in one other unrelated individual who was referred forCatecholaminergic polymorphic ventricular tachycardia (CPVT) genetic testing at GeneDx; however,segregation information is absent. The S1638T variant was not observed in approximately 6,000individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This substitution occurs at aposition that is conserved in mammals. However, Threonine is the wildtype amino acid at thisposition in at least two species. In addition, the S1638T variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. Furthermore, the S1638T variant is not located in one ofthe three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variantsoccur (Medeiros-Domingo et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or benign.
Invitae RCV000639029 SCV000760587 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-10-26 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1638 of the RYR2 protein (p.Ser1638Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201252). 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 tolerated, 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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