ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.37T>C (p.Phe13Leu) (rs794728761)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242738 SCV000318757 uncertain significance Cardiovascular phenotype 2013-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Invitae RCV000551463 SCV000637557 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 13 of the RYR2 protein (p.Phe13Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. While this variant is not present in population databases (rs794728761), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201289). This variant does not occur within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000780697 SCV000918178 uncertain significance not specified 2018-01-10 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.37T>C (p.Phe13Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain of the protein (interPro). This variant is absent in 39280 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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