ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1822C>T (p.His608Tyr) (rs727504718)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156007 SCV000205719 uncertain significance not specified 2013-10-10 criteria provided, single submitter clinical testing The His608Tyr variant in RYR2 has not been reported in individuals with cardiomy opathy and data from large population studies is insufficient to assess the freq uency of this variant. Computational analyses (biochemical amino acid properties , conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support fo r or against an impact to the protein, though 1 fish (stickleback) carries a tyr osine (Tyr; this variant), raising the possibility that the change may be tolera ted. Additional information is needed to fully assess the clinical significance of the His608Tyr variant.
GeneDx RCV000766708 SCV000235070 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing The H608Y variant of uncertain significance in the RYR2 gene has not been published as pathogenic or been reported as benign to our knowledge. The H608Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the H608Y variant. In addition, this variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, the H608Y variant was observed in 4/2,222 (0.18%) alleles from African ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Invitae RCV001083748 SCV000637535 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000156007 SCV000920167 benign not specified 2018-09-04 criteria provided, single submitter clinical testing Variant summary: RYR2 c.1822C>T (p.His608Tyr) results in a conservative amino acid change located in the RIH and B30.2/SPRY domains of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 178558 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0019 in the gnomAD database. This frequency within African control individuals is approximately 76-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.1822C>T, has been reported in the literature in individuals affected with Cardiomyopathy without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with classifications of uncertain significance (2x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Color RCV001177069 SCV001341197 likely benign Cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477834 SCV000536815 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2; Catecholaminergic polymorphic ventricular tachycardia type 1 2016-04-27 no assertion criteria provided research

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.