ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3266G>A (p.Arg1089His) (rs552564367)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774257 SCV000907958 uncertain significance Cardiomyopathy 2018-10-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic SPRY domain 2 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/276942 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000806738 SCV000946753 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1089 of the RYR2 protein (p.Arg1089His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs552564367, ExAC 0.001%). This variant has been observed in an individual in a cohort of patient with catecholaminergic polymorphic ventricular tachycardia  (PMID: 28404607). 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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