Submissions for variant NM_001035.3(RYR2):c.10373G>A (p.Arg3458Gln)

gnomAD frequency: 0.00002  dbSNP: rs762944627

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519878	SCV000616956	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The R3458Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,000 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R3458Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, R3458Q is 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).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color Diagnostics, LLC DBA Color Health	RCV000772057	SCV000905085	uncertain significance	Cardiomyopathy	2022-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 3458 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 been identified in 4/248720 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.
Invitae	RCV003105937	SCV003780240	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-25	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 3458 of the RYR2 protein (p.Arg3458Gln). This variant is present in population databases (rs762944627, gnomAD 0.01%). 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: 449143). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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.