Submissions for variant NM_001035.3(RYR2):c.4692G>A (p.Met1564Ile)

gnomAD frequency: 0.00004  dbSNP: rs201675951

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766716	SCV000235108	uncertain significance	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Reported in patients with cardiomyopathy and arrhythmia, including primary electrical disease (Haas et al., 2015; Proost et al., 2017; van Lint et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); This variant is associated with the following publications: (PMID: 28404607, 25925909, 28341588, 25163546, 30847666, 26582918, 32152366)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182725	SCV000272389	uncertain significance	not specified	2017-10-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV002514771	SCV000935695	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1564 of the RYR2 protein (p.Met1564Ile). This variant is present in population databases (rs201675951, gnomAD 0.02%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 25163546, 28341588, 30847666, 32152366). ClinVar contains an entry for this variant (Variation ID: 155831). 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 80%. 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	RCV001186230	SCV001352598	uncertain significance	Cardiomyopathy	2023-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1564 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals who had no cardiovascular disorders but with a family history of sudden cardiac death (PMID: 33829027). This variant has been identified in 21/235890 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182725	SCV002511578	likely benign	not specified	2022-04-18	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4692G>A (p.Met1564Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 235890 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4692G>A has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia, dilated cardiomyopathy, Cyclic vomiting syndrome or Primary electrical disease (Haas_2014, Lee_2015, Proost_2017, Landstrom_2017, Olubando_2020). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Blueprint Genetics	RCV000143946	SCV000188826	uncertain significance	Primary dilated cardiomyopathy	2014-11-27	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157455	SCV000207199	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-11-27	no assertion criteria provided	clinical testing