Submissions for variant NM_001035.3(RYR2):c.8262G>C (p.Gln2754His)

gnomAD frequency: 0.00003  dbSNP: rs773748242

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182880	SCV000235268	uncertain significance	not provided	2014-10-02	criteria provided, single submitter	clinical testing	p.Gln2754His (CAG>CAC): c.8262 G>C in exon 55 of the RYR2 gene (NM_001035.2). The Q2754H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q2754H variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q2754H 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 within mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. This variant does not reside in one of the three mutational hot spots in the RYR2 gene (Medeiros-Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae	RCV002515342	SCV000954303	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with histidine at codon 2754 of the RYR2 protein (p.Gln2754His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs773748242, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201390). 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 not expected to disrupt 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.
Color Diagnostics, LLC DBA Color Health	RCV001175683	SCV001339374	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 2754 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 been reported in an individual suspected of having catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). This variant has been identified in 9/258936 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.
Baylor Genetics	RCV001337100	SCV001530677	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-03-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002426879	SCV002681435	uncertain significance	Cardiovascular phenotype	2022-07-28	criteria provided, single submitter	clinical testing	The p.Q2754H variant (also known as c.8262G>C), located in coding exon 55 of the RYR2 gene, results from a G to C substitution at nucleotide position 8262. The glutamine at codon 2754 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a catecholaminergic polymorphic ventricular tachycardia (CPVT) cohort, as well as a whole exome sequencing cohort; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[ePub ahead of print]; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.