ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.719A>C (p.His240Pro) (rs369512347)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182664 SCV000235043 likely pathogenic not provided 2013-06-17 criteria provided, single submitter clinical testing p.His240Pro (CAC>CCC): c.719 A>C in exon 10 of the RYR2 gene (NM_001035.2). The His240Pro variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, a mutation at this same residue (His240Arg) has been reported in an infant who was compound heterozygous for His240Arg and Thr4158Pro in the RYR2 gene. The infant died unexpectedly at the age of 2 years with no family history of cardiac events (Tester D et al., 2012). His240Pro is located in one of three mutation hot-spots in the RYR2 gene (Medeiros-Domingo A et al., 2009), and mutations in nearby residues (Gly230Cys, Asp242Val, Glu243Lys) have been reported in association with CPVT, supporting the functional importance of this region of the protein. Additionally, the His240Pro 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, His240Pro is a good candidate for a disease-causing mutation. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to--cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 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 ARVC,CPVT panel(s).

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