ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1454G>A (p.Arg485Gln) (rs752144775)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182863 SCV000235251 uncertain significance not specified 2015-09-10 criteria provided, single submitter clinical testing This missense change is denoted Arg485Gln (aka R485Q) at the protein level and c.1454 G>A at the cDNA level. The Arg485Gln variant in the RYR2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg485Gln results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a residue that is conserved across species. The Arg485Gln variant was not detected in up 400 alleles from control individuals of Caucasian ancestry tested at GeneDx, indicating it is not a common benign variant in this population. However, the Arg485Gln is not located in one of the three mutation hot spots in the RYR2 gene (Medeiros-Domingo, et al. 2009). With the clinical and molecular information available at this time, we cannot unequivocally determine whether the Arg485Gln variant in the RYR2 gene is a disease-causing mutation or a rare benignvariant. The variant is found in CPVT panel(s).
Blueprint Genetics RCV000208338 SCV000264179 uncertain significance Ventricular tachycardia 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000475611 SCV000541669 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 485 of the RYR2 protein (p.Arg485Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs752144775, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 30403697); however, this individual had an additional RYR2 variant. ClinVar contains an entry for this variant (Variation ID: 201374). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000777944 SCV000914042 uncertain significance Cardiomyopathy 2020-04-13 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000777944 SCV000995096 uncertain significance Cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777944 SCV001333882 uncertain significance Cardiomyopathy 2019-01-08 criteria provided, single submitter clinical testing

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