ClinVar

Description

p.Ala271Val (GCA>GTA): c.812 C>T in exon 11 of the RYR2 gene (NM_001035.2). The Ala271Val variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala271Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is well conserved across species. In silico algorithms are not consistent in their predictions but at least two concur that Ala271Val is damaging to the protein structure/function. No mutations in nearby residues have been reported in association with CPVT; however, Ala271Val is located in the N-terminal mutation hot-spot" domain in the RYR2 gene (Medeiros-Domingo A et al., 2009). Lastly, the Ala271Val 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. With the clinical and molecular information available at this time, we cannot definitively determine if Ala271Val is a disease-causing 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). 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)."