Submissions for variant NM_001035.3(RYR2):c.3425C>T (p.Ala1142Val)

dbSNP: rs772148152

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182713	SCV000235095	uncertain significance	not provided	2013-02-13	criteria provided, single submitter	clinical testing	p.Ala1142Val (GCC>GTC): c.3425 C>T in exon 29 of the RYR2 gene (NM_001035.2). The Ala1142Val variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala1142Val results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is conserved in mammals. Two in silico analysis programs predict Ala1142Val is benign to the protein structure/function, while another predicts it is possibly damaging. In addition, there have been no nearby mutations reported in association with arrhythmia, indicating this region of the protein may be tolerant of change. However, the Ala1142Val 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 Ala1142Val is a disease-causing mutation or a rare benign variant. 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 panel(s).
Color Diagnostics, LLC DBA Color Health	RCV000778052	SCV000914167	uncertain significance	Cardiomyopathy	2022-04-07	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.