ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1791T>G (p.Ile597Met) (rs794728725)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182690 SCV000235069 uncertain significance not provided 2012-12-17 criteria provided, single submitter clinical testing p.Ile597Met (ATT>ATG): c.1791 T>G in exon 18 of the RYR2 gene (NM_001035.2). The Ile597Met variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile597Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Ile597Met is damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Ile597Met was not observed in approximately 5,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, Ile597Met is not located in one of the hot spot" regions of the RYR2 gene, where the majority of mutations have been identified in association with CPVT. With the clinical and molecular information available at this time, we cannot definitively determine if Ile597Met is a disease-causing 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). Mutations in the KCNH2 gene have been reported in approximately 25-35% of patients with autosomal dominant long QT syndrome, and are associated with increased risk of cardiac events triggered by exercise and auditory stimulation, especially during sleep (Vincent G, 2009). 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 POSTMORTEM panel(s)."

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