ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8408G>A (p.Arg2803Gln) (rs780643623)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182768 SCV000235154 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Although the R2803Q variant of uncertain significance in the RYR2 gene has not been published as pathogenic in association with arrhythmia or been reported as benign to our knowledge, it has been identified independently of additional cardiogenetic variants in one other individual referred for arrhythmia genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R2803Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2803Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, the R2803Q variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000689347 SCV000816995 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2803 of the RYR2 protein (p.Arg2803Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs780643623, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201285). 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 C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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