ClinVar Miner

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

dbSNP: rs794728761
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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 The p.F13L variant (also known as c.37T>C) is located in exon 1 of the RYR2 gene. This alteration results from a T to C substitution at nucleotide position 37. The phenylalanine at codon 13 is replaced by leucine, an amino acid with highly similar properties.This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not observed in 6093 samples (12186 alleles) with coverage at this position.​ This amino acid position is well conserved in available vertebrate species based on a limited protein alignment. In addition, this variant ispredicted to be possibly damaging and toleratedby PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV002516887 SCV000637557 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2022-02-08 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 201289). This missense change has been observed in individuals with RYR2-related conditions (PMID: 31112425; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 13 of the RYR2 protein (p.Phe13Leu). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.