ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs770863319
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Total submissions: 9
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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.
Invitae RCV002516881 SCV001539190 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-29 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

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