Submissions for variant NM_001035.3(RYR2):c.6800G>A (p.Arg2267His)

gnomAD frequency: 0.00002  dbSNP: rs759012078

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002534594	SCV000935575	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184874	SCV001350961	uncertain significance	Cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2267 of the RYR2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown that the mutant protein exhibits normal calcium channel function under basal conditions but shows significantly increased activity during stress (PMID: 17556193). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 17556193). This variant has also been reported in 5 related individuals who had have had negative exercise stress tests, echocardiograms and Holter monitors, suggesting that this variant may lack pathogenicity (PMID: 32220801). This variant has been identified in 7/246002 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.
Genetic Services Laboratory, University of Chicago	RCV001816852	SCV002064383	pathogenic	not provided	2019-02-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RYR2 gene demonstrated a sequence change, c.6800G>A, in exon 45 that results in an amino acid change, p.Arg2267His. This sequence change has been described in the gnomAD database with a low population frequency of 0.003% (dbSNP rs759012078). This pathogenic sequence change has previously been described in a 6 week old baby who died from possible sudden infant death syndrome (SIDS) (Tester et al., 2007). Tester, et al., 2007, performed functional analysis using RyR2-R2267H mutant HEK293 cells and demonstrated that the cells showed increased RyR2 channel activity with protein kinase A (PKA) phosphorylation, which simulated conditions of stress. The p.Arg2267His change affects a highly conserved amino acid residue located in the calstabin-2-binding domain of the RYR2 protein that is known to be functional. The p.Arg2267His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
All of Us Research Program, National Institutes of Health	RCV004001598	SCV004818897	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2267 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the mutant protein exhibits normal calcium channel function under basal conditions but shows significantly increased activity during stress (PMID: 17556193). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 17556193). This variant has also been reported in 5 related individuals who had have had negative exercise stress tests, echocardiograms and Holter monitors, suggesting that this variant may lack pathogenicity (PMID: 32220801). This variant has been identified in 7/246002 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	RCV004027553	SCV005037047	uncertain significance	Cardiovascular phenotype	2024-02-16	criteria provided, single submitter	clinical testing	The p.R2267H variant (also known as c.6800G>A), located in coding exon 45 of the RYR2 gene, results from a G to A substitution at nucleotide position 6800. The arginine at codon 2267 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a sudden infant death cohort; however, clinical details were limited (Tester DJ et al. Heart Rhythm, 2007 Jun;4:733-9). This amino acid position is not 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 alteration remains unclear.