Submissions for variant NM_001035.3(RYR2):c.6320C>T (p.Thr2107Met)

gnomAD frequency: 0.00006  dbSNP: rs370331492

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154820	SCV000204501	uncertain significance	not specified	2013-07-18	criteria provided, single submitter	clinical testing	The Thr2107Met variant in RYR2 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8286 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computationa l analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen 2, and SIFT) suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. Additional informati on is needed to fully assess the variant's clinical significance.
Invitae	RCV002516109	SCV000541676	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2107 of the RYR2 protein (p.Thr2107Met). This variant is present in population databases (rs370331492, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy with right dominant form and/or clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 31737537, 35819174). ClinVar contains an entry for this variant (Variation ID: 178121). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765090	SCV000896299	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179780	SCV001344553	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This variant is located in 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (Marschall et al., 2019). This variant has also been identified in 22/249170 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256936	SCV001433457	uncertain significance	Conduction disorder of the heart	2019-09-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001335571	SCV001528745	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-07-06	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001762335	SCV002008092	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Reported in association with arrythmogenic cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Landstrom et al., 2017; Marschall et al., 2019; Goudal et al., 2022); however, this variant has also been reported in healthy individuals (Bajaj et al., 2022).; 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: 19926015, 26582918, 35932045, 35819174, 28404607, 31737537)
Ambry Genetics	RCV002362815	SCV002660624	uncertain significance	Cardiovascular phenotype	2021-11-23	criteria provided, single submitter	clinical testing	The p.T2107M variant (also known as c.6320C>T), located in coding exon 41 of the RYR2 gene, results from a C to T substitution at nucleotide position 6320. The threonine at codon 2107 is replaced by methionine, an amino acid with similar properties. This alteration has been detected in a cohort referred for whole exome sequencing and in a cohort referred for suspicion of various arrhythmogenic disorders (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.