Submissions for variant NM_001035.3(RYR2):c.9251G>A (p.Arg3084Gln)

gnomAD frequency: 0.00005  dbSNP: rs747605864

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621329	SCV000736415	uncertain significance	Cardiovascular phenotype	2023-02-24	criteria provided, single submitter	clinical testing	The p.R3084Q variant (also known as c.9251G>A), located in coding exon 65 of the RYR2 gene, results from a G to A substitution at nucleotide position 9251. The arginine at codon 3084 is replaced by glutamine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV001179342	SCV001343989	uncertain significance	Cardiomyopathy	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 3084 of 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 not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 5/232806 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195399	SCV001365749	uncertain significance	not specified	2019-04-17	criteria provided, single submitter	clinical testing	The p.Arg3084Gln variant in RYR2 has not been previously reported in individuals with CPVT or ARVC but has been identified in 5/232806 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 518852). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
Invitae	RCV002531752	SCV001546686	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3084 of the RYR2 protein (p.Arg3084Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 518852). 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.
GeneDx	RCV002285372	SCV002576025	uncertain significance	not provided	2022-04-06	criteria provided, single submitter	clinical testing	Identified in an adult patient with DCM, though p.(R3084Q) was absent in her affected sister (Pena-Pena et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on 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); This variant is associated with the following publications: (PMID: 32826072)