Submissions for variant NM_001035.3(RYR2):c.8408G>A (p.Arg2803Gln)

gnomAD frequency: 0.00002  dbSNP: rs780643623

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182768	SCV000235154	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Although the R2803Q variant of uncertain significance in the RYR2 gene has not been published as pathogenic in association with arrhythmia or been reported as benign to our knowledge, it has been identified independently of additional cardiogenetic variants in one other individual referred for arrhythmia genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R2803Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2803Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, the R2803Q variant 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). Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV002515330	SCV000816995	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170262	SCV001332823	uncertain significance	Cardiomyopathy	2017-12-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170262	SCV001358293	uncertain significance	Cardiomyopathy	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2803 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 RYR2-related disorders in the literature. This variant has been identified in 2/128032 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.