ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4503C>A (p.Asn1501Lys) (rs794728735)

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 RCV000182722 SCV000235105 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing p.Asn1501Lys (AAC>AAA): c.4503 C>A in exon 34 of the RYR2 gene (NM_001035.2). The N1501K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The N1501K variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1501K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with CPVT, indicating that 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. 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). Mutations in the CASQ2 gene have been reported in approximately 1-2% of patients with autosomal recessive CPVT (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).

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.