ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4828C>T (p.Arg1610Ter) (rs794728738)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182728 SCV000235112 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing p.Arg1610Stop (CGA>TGA): c.4828 C>T in exon 36 of the RYR2 gene (NM_001035.2). The R1610X variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. R1610X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, the majority of disease-causing mutations in the RYR2 gene are either missense changes or small in-frame deletions/duplications that alter calcium release from the sarcoplasmic reticulum (SR). Similarly, the published in-frame deletion of exon three is predicted to decrease the threshold for termination of calcium release from the SR and thus increase the cytosolic calcium transient (Tang Y et al., 2012). Haploinsufficiency for RYR2 has not been definitively shown to cause cardiomyopathy in humans. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV001059606 SCV001224233 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-01-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1610*) in the RYR2 gene. It is expected to result in an absent or disrupted protein product. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 201251). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease. 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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