ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.505C>T (p.Arg169Ter)

gnomAD frequency: 0.00001  dbSNP: rs749930577
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755694 SCV000883126 uncertain significance Arrhythmogenic right ventricular dysplasia 2 2018-11-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001525929 SCV001736136 uncertain significance Cardiomyopathy 2020-12-22 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 8 of the RYR2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/248902 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the RYR2 gene is not clearly established. 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.
Ambry Genetics RCV003166001 SCV003858430 uncertain significance Cardiovascular phenotype 2022-11-02 criteria provided, single submitter clinical testing The p.R169* variant (also known as c.505C>T), located in coding exon 8 of the RYR2 gene, results from a C to T substitution at nucleotide position 505. This changes the amino acid from an arginine to a stop codon within coding exon 8. This variant has been detected in an exome sequencing cohort not selected for the presence of cardiovascular disease; however details were limited (Thauvin-Robinet C et al. Eur J Hum Genet, 2019 08;27:1197-1214). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of RYR2 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003525960 SCV004299988 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-04-15 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with RYR2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 617902). This variant is present in population databases (rs749930577, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg169*) in the RYR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease.

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