ClinVar Miner

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

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Total submissions: 5
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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 2017-11-28 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 not been reported in the literature in individuals with RYR2-related disease. 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 2018-10-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
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

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