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 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 RCV000551463 SCV001338371 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2020-02-17 criteria provided, single submitter clinical testing Variant summary: RYR2 c.37T>C (p.Phe13Leu) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 39990 control chromosomes (gnomAD). c.37T>C has been reported in the literature in five individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia from one family, and authors classified the variant as likely pathogenic based on phenotype-enhanced ACMG variant classification framework (Giudicessi_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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