ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.704G>A (p.Arg235Lys) (rs794728711)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182663 SCV000235042 likely pathogenic not provided 2013-07-05 criteria provided, single submitter clinical testing p.Arg235Lys (AGG>AAG): c.704 G>A in exon 10 of the RYR2 gene (NM_001035.2). The Arg235Lys variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg235Lys results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg235Lys is possibly damaging to the protein structure/function. Arg235Lys is located in the N-terminal mutation hot spot" domain" (Medeiros-Domingo A et al., 2009). Also, mutations in nearby residues (Gly230Cys, His240Arg) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. The Arg235Lys 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. In summary, while Arg235Lys is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium-ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). 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). 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 panel(s)."

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