ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1166G>A (p.Arg389His) (rs200685968)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154810 SCV000204490 uncertain significance not specified 2014-01-02 criteria provided, single submitter clinical testing The Arg389His variant in RYR2 has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/8200 European American chromosom es by the NHLBI Exome Sequencing Project (; dbS NP rs200685968). This frequency is too low to rule out a role in disease. The af fected amino acid is well conserved in evolution, suggesting that a change may n ot be tolerated. This is consistent with computational predictions suggesting t hat the change to histidine (His) may impact the protein. In addition, this var iant is predicted to create a novel splice site that would disrupt the exon if u sed. However, the accuracy of these tools is unknown. In summary, additional in formation is needed to fully assess the clinical significance of the Arg389His v ariant.
Fulgent Genetics,Fulgent Genetics RCV000765085 SCV000896294 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2; Catecholaminergic polymorphic ventricular tachycardia type 1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001062852 SCV001227675 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 389 of the RYR2 protein (p.Arg389His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200685968, ExAC 0.007%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 178114). 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.
Color RCV001189965 SCV001357365 uncertain significance Cardiomyopathy 2019-11-19 criteria provided, single submitter clinical testing

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