ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10897G>A (p.Glu3633Lys) (rs748501600)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246010 SCV000319047 uncertain significance Cardiovascular phenotype 2013-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000182836 SCV000235223 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted Glu3633Lys (aka E3633K) at the protein level and c.10897 G>A at the cDNA level. The Glu3633Lys variant in the RYR2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Glu3633Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a residue that is conserved across species. However, the Glu3633Lys variant does not occur in or near any of the three mutation hot spot regions in the RYR2 gene. We cannot unequivocally determine whether the Glu3633Lys variant is disease-causing mutations or benign variants. The variant is found in CPVT panel(s).
Invitae RCV000706045 SCV000835074 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 3633 of the RYR2 protein (p.Glu3633Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs748501600, ExAC 0.003%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201348). 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 C55"). 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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