Submissions for variant NM_001035.3(RYR2):c.10189C>T (p.Arg3397Cys)

gnomAD frequency: 0.00001  dbSNP: rs764084155

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001776365	SCV002012881	uncertain significance	not provided	2019-05-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV001776365	SCV002541784	uncertain significance	not provided	2021-04-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003120684	SCV003789251	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298995	SCV003997089	uncertain significance	Cardiovascular phenotype	2023-05-30	criteria provided, single submitter	clinical testing	The p.R3397C variant (also known as c.10189C>T), located in coding exon 70 of the RYR2 gene, results from a C to T substitution at nucleotide position 10189. The arginine at codon 3397 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an arrhythmogenic cardiomyopathy cohort (Chen K et al. Europace, 2019 Jun;21:970-977). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV003533026	SCV004360755	uncertain significance	Cardiomyopathy	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 3397 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/246902 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.
All of Us Research Program, National Institutes of Health	RCV004009042	SCV004815244	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 3397 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/246902 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.