Submissions for variant NM_001035.3(RYR2):c.5588C>T (p.Thr1863Met)

gnomAD frequency: 0.00004  dbSNP: rs770863319

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724909	SCV000235116	uncertain significance	not provided	2022-06-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter 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)
Eurofins Ntd Llc (ga)	RCV000724909	SCV000332334	uncertain significance	not provided	2015-06-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618427	SCV000738019	uncertain significance	Cardiovascular phenotype	2018-09-13	criteria provided, single submitter	clinical testing	The p.T1863M variant (also known as c.5588C>T), located in coding exon 37 of the RYR2 gene, results from a C to T substitution at nucleotide position 5588. The threonine at codon 1863 is replaced by methionine, an amino acid with similar properties. This alteration was detected in an exome cohort not selected for cardiovascular disease, though clinical details were not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol. 2017;10(4):e004742). This amino acid position is poorly 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000182732	SCV000740442	uncertain significance	not specified	2016-09-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001187136	SCV001353825	uncertain significance	Cardiomyopathy	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1863 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516881	SCV001539190	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-29	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000724909	SCV002503558	uncertain significance	not provided	2021-02-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182732	SCV002766112	uncertain significance	not specified	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.5588C>T (p.Thr1863Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248356 control chromosomes. The observed variant frequency is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), suggesting that the variant may be benign. c.5588C>T has been reported in the literature in a Catecholaminergic Polymorphic Ventricular Tachycardia cohort (Mazzanti_2022). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
CeGaT Center for Human Genetics Tuebingen	RCV000724909	SCV004033014	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	RYR2: BP4, BS2
All of Us Research Program, National Institutes of Health	RCV003996760	SCV004820021	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1863 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.