ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2399T>C (p.Val800Ala) (rs794728730)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182698 SCV000235077 uncertain significance not provided 2014-05-08 criteria provided, single submitter clinical testing p.Val800Ala (GTA>GCA): c.2399 T>C in exon 22 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The V800A variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although V800A results in a conservative amino acid substitution of one non-polar amino acid with another, it occurs at a position that is conserved across species. The V800A variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, in silico analysis predicts this variant is benign to the protein structure/function. Furthermore, no disease-causing mutations have been reported in neighboring residues, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Familial Long QT syndrome is primarily an autosomal dominant disease caused by mutation(s) in cardiac ion channel genes. Mutations in these genes tend to prolong the duration of the ventricular action potential, thus lengthening the QT interval seen on an ECG (Goldenberg I et al., 2008; Priori S et al., 2004). LQTS is associated with increased risk for syncope, ventricular arrhythmia and sudden cardiac death in young adults with normal heart structure (Vincent G, 1998). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Although rare, mutations in the ANK2 gene have been reported previously in association with LQTS (Mohler P et al., 2003). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT,POSTMORTEM panel(s).
Invitae RCV001070723 SCV001235991 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 800 of the RYR2 protein (p.Val800Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Color RCV001186514 SCV001352963 uncertain significance Cardiomyopathy 2019-12-16 criteria provided, single submitter clinical testing

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