ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6598C>T (p.Leu2200Phe) (rs794728743)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182744 SCV000235129 likely pathogenic not provided 2012-06-06 criteria provided, single submitter clinical testing p.Leu2200Phe (CTC>TTC): c.6598 C>T in exon 43 of the RYR2 gene (NM_001035.2). The Leu2200Phe variant in the RYR2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Leu2200Phe results in a semi-conservative amino acid substitution of a non-polar Leucine with an aromatic, non-polar Phenylalanine at a residue that is conserved across species. The NHLBI ESP Exome Variant Server reports Leu2200Phe was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. While Leu2200Phe does not occur in one of the RYR2 mutation hot spots, a mutation in a nearby codon (Asp2216Val) has been reported in association with CPVT, supporting the functional importance of this region of the protein (Medeiros-Domingo A et al., 2009). In summary, the clinical significance of the Leu2200Phe variant in the RYR2 gene is currently unknown, though the evidence suggests this is a good candidate for a disease-causing mutation. 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 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 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.