Submissions for variant NM_001035.3(RYR2):c.3361G>C (p.Gly1121Arg)

gnomAD frequency: 0.00003  dbSNP: rs199682282

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431787	SCV000536513	uncertain significance	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with a RYR2-related disorder to our knowledge; 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28404607)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103760	SCV001221339	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182765	SCV001348327	uncertain significance	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1121 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 6/280628 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000431787	SCV002541780	uncertain significance	not provided	2021-06-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323667	SCV002607272	uncertain significance	Cardiovascular phenotype	2024-04-26	criteria provided, single submitter	clinical testing	The p.G1121R variant (also known as c.3361G>C), located in coding exon 28 of the RYR2 gene, results from a G to C substitution at nucleotide position 3361. The glycine at codon 1121 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004000595	SCV004823660	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1121 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/280628 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.