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

gnomAD frequency: 0.00046  dbSNP: rs727504718

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-03-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19926015)
Invitae	RCV002515008	SCV000637535	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Diagnostics, LLC DBA Color Health	RCV001177069	SCV001341197	likely benign	Cardiomyopathy	2018-11-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408693	SCV002711091	likely benign	Cardiovascular phenotype	2020-08-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000766708	SCV003820588	uncertain significance	not provided	2019-04-25	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477834	SCV000536815	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1	2016-04-27	no assertion criteria provided	research