ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5011C>T (p.Arg1671Trp) (rs747404408)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560632 SCV000637572 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1671 of the RYR2 protein (p.Arg1671Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs747404408, ExAC 0.001%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 463604). 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.
Ambry Genetics RCV000621122 SCV000734915 uncertain significance Cardiovascular phenotype 2016-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000772107 SCV000905143 uncertain significance Cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in a domain of unknown function in exon 37 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 the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disease in the literature. This variant is rare in the general population (5/276992 chromosomes in the Genome Aggregation Database, gnomAD). Based on available information, this variant is classified as Variant of Uncertain Significance.

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