Submissions for variant NM_001035.3(RYR2):c.1939C>T (p.Arg647Cys)

gnomAD frequency: 0.00020  dbSNP: rs202040519

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154813	SCV000204493	uncertain significance	not specified	2013-04-03	criteria provided, single submitter	clinical testing	The Arg647Cys variant in RYR2 has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/8366 Eu ropean American chromosomes and 1/3992 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs202040519). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000656970	SCV000565509	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	Identified in a cohort of stillbirths without chromosomal abnormalities (PMID: 30615648); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); 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: 19926015, 28404607, 30847666, 30122538, 32152366, 33789662, 30615648)
Ambry Genetics	RCV000619369	SCV000735564	uncertain significance	Cardiovascular phenotype	2024-05-07	criteria provided, single submitter	clinical testing	The c.1939C>T (p.R647C) alteration is located in exon 19 (coding exon 19) of the RYR2 gene. This alteration results from a C to T substitution at nucleotide position 1939, causing the arginine (R) at amino acid position 647 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470780	SCV000760675	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 647 of the RYR2 protein (p.Arg647Cys). This variant is present in population databases (rs202040519, gnomAD 0.03%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 30847666, 32152366). ClinVar contains an entry for this variant (Variation ID: 178115). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000771900	SCV000904664	uncertain significance	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 647 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 41/279906 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470780	SCV002767853	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 2 (MIM#600996) and ventricular tachycardia, catecholaminergic polymorphic, 1 (MIM#604772) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (41 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RIH domain (NCBI, PDB). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.Arg647His) has been reported multiple times as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS (LOVD, ClinVar, PMID: 30615648, PMID: 28404607), once as likely benign (LOVD) and once as likely pathogenic in a patient from a large arrhythmia cohort (PMID: 30847666). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002478454	SCV002778042	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656970	SCV003820598	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147363	SCV003835566	uncertain significance	Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2022-10-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147362	SCV003835773	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2022-10-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002470780	SCV003835848	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-10	criteria provided, single submitter	clinical testing