Submissions for variant NM_001035.3(RYR2):c.4465T>C (p.Cys1489Arg)

gnomAD frequency: 0.00014  dbSNP: rs200450676

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154819	SCV000204500	uncertain significance	not specified	2019-01-25	criteria provided, single submitter	clinical testing	The p.Cys1489Arg variant in RYR2 has now been identified by our laboratory in 1 Black individual and 1 Caucasian individual with DCM (LMM unpublished data). In addition, it has also been identified in 1/8376 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200450676). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000725016	SCV000235104	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Reported in individuals with HCM, sudden unexplained death (SUD), arrhythmogenic cardiomyopathy and sudden unexplained death in epilepsy (SUDEP) in published literature (Lopes et al., 2015; Bagnall et al., 2016; Sanchez et al., 2016; Goudal et al., 2022); however, no segregation studies were described; Also identified in a cohort of individuals undergoing clinical exome sequencing (Landstrom et al., 2017); although, the indication for testing, follow-up cardiac evaluations and segregation studies were not reported; 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27482086, 28404607, 26704558, 27930701, 35819174, 25351510)
Eurofins Ntd Llc (ga)	RCV000725016	SCV000333232	uncertain significance	not provided	2015-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515200	SCV000611433	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1	2017-05-23	criteria provided, single submitter	clinical testing
Invitae	RCV002514978	SCV000637566	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768765	SCV000900135	uncertain significance	Cardiomyopathy	2017-07-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768765	SCV000914107	likely benign	Cardiomyopathy	2020-01-27	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000725016	SCV000987636	uncertain significance	not provided		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725016	SCV001471374	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing	The RYR2 c.4465T>C; p.Cys1489Arg variant (rs200450676) is reported in the literature in an individual affected with hypertrophic cardiomyopathy and another individual with sudden unexpected death in epilepsy (Bagnall 2016, Lopes 2015). This variant is found in the Latino population with an overall allele frequency of 0.04% (15/34756 alleles) in the Genome Aggregation Database. The cysteine at codon 1489 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Cys1489Arg variant is uncertain at this time. References: Bagnall et al., Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol. 2016 Apr;79(4):522-34. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301.
Mayo Clinic Laboratories, Mayo Clinic	RCV000725016	SCV001715665	uncertain significance	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326882	SCV002638467	uncertain significance	Cardiovascular phenotype	2022-03-24	criteria provided, single submitter	clinical testing	The p.C1489R variant (also known as c.4465T>C), located in coding exon 34 of the RYR2 gene, results from a T to C substitution at nucleotide position 4465. The cysteine at codon 1489 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been identified in a hypertrophic cardiomyopathy cohort, in an individual from a sudden unexplained death in epilepsy cohort with history of nocturnal seizures, and in an exome sequencing cohort; however clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Bagnall RD et al. Ann. Neurol., 2016 Apr;79:522-34). This alteration has also been seen in a sudden unexplained death cohort with variants in other cardiac-related genes (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678836	SCV000805024	likely pathogenic	Long QT syndrome	2017-04-12	no assertion criteria provided	clinical testing