ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9569G>A (p.Arg3190Gln) (rs369276868)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182883 SCV000235271 uncertain significance not provided 2015-02-19 criteria provided, single submitter clinical testing This missense change is denoted Arg3190Gln (aka R3190Q) at the protein level and c.9569 G>A at the cDNA level. The Arg3190Gln variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Arg3190Gln results in a non-conservative amino acid substitution of a positively charged Arginine residue with a neutral, polar Glutamine residue at a position that is class conserved in mammals. Arg3190Gln was not observed in up to 600 control alleles from individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign polymorphism in these populations. Nevertheless, Arg3190Gln is located in a region of the protein without reported mutations in surrounding codons, indicating this region may be tolerant of change. In summary, we cannot determine if Arg3190Gln in RYR2 is a disease-causing mutation or a rare benign variant, and further studies are needed to clarify the biological relevance of this variant. The variant is found in ARVC panel(s).
Color RCV000778056 SCV000914171 uncertain significance Cardiomyopathy 2020-03-06 criteria provided, single submitter clinical testing
Invitae RCV001068690 SCV001233816 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3190 of the RYR2 protein (p.Arg3190Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs369276868, ExAC 0.02%). This variant has been observed in an individual with sudden cardiac death (PMID: 28237968). ClinVar contains an entry for this variant (Variation ID: 201393). 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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