ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3425C>T (p.Ala1142Val) (rs772148152)

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Total submissions: 2
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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 RCV000778052 SCV000914167 uncertain significance Cardiomyopathy 2018-10-25 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is located in the cytoplasmic SPRY domain 2 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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