Submissions for variant NM_001035.3(RYR2):c.893G>A (p.Arg298His)

gnomAD frequency: 0.00001  dbSNP: rs754259295

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182670	SCV000235049	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing	p.Arg298His (CGC>CAC): c.893 G>A in exon 12 of the RYR2 gene (NM_001035.2). The Arg298His variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg298His results in a conservative amino acid substitution of one positively-charged amino acid for another, this substitution occurs at a position that is conserved across species. However, there have been no nearby mutations reported in association with arrhythmia, indicating this region of the protein may be tolerant of change. Nevertheless, in silico analysis predicts Arg298His is probably damaging to the protein structure/function. Furthermore, the Arg298His variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Arg298His is a disease-causing mutation or a rare benign variant. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium-ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517788	SCV001216753	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-07-07	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 201205). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs754259295, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 298 of the RYR2 protein (p.Arg298His).
Color Diagnostics, LLC DBA Color Health	RCV001524921	SCV001734901	uncertain significance	Cardiomyopathy	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 298 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 5/280366 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.
Ambry Genetics	RCV002372116	SCV002683940	uncertain significance	Cardiovascular phenotype	2021-04-20	criteria provided, single submitter	clinical testing	The p.R298H variant (also known as c.893G>A), located in coding exon 12 of the RYR2 gene, results from a G to A substitution at nucleotide position 893. The arginine at codon 298 is replaced by histidine, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182670	SCV004224825	uncertain significance	not provided	2023-01-12	criteria provided, single submitter	clinical testing	PP3
All of Us Research Program, National Institutes of Health	RCV003996740	SCV004845753	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 298 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 cardiovascular disorders in the literature. This variant has been identified in 5/280366 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.
PreventionGenetics, part of Exact Sciences	RCV004739569	SCV005358627	uncertain significance	RYR2-related disorder	2024-05-13	no assertion criteria provided	clinical testing	The RYR2 c.893G>A variant is predicted to result in the amino acid substitution p.Arg298His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.