Submissions for variant NM_001035.3(RYR2):c.5762G>A (p.Arg1921Gln)

gnomAD frequency: 0.00003  dbSNP: rs370568809

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182736	SCV000235120	uncertain significance	not provided	2016-12-09	criteria provided, single submitter	clinical testing	p.Arg1921Gln (CGG>CAG): c.5762 G>A in exon 38 of the RYR2 gene (NM_001035.2). The R1921Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1921Q variant was not observed with any significant frequency 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. The R1921Q 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 in the cytoplasmic domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic 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). 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 POSTMORTEM panel(s).
Invitae	RCV002517793	SCV001226809	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-07-25	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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 201259). This missense change has been observed in individual(s) with sudden death (PMID: 29544603, 32152366). This variant is present in population databases (rs370568809, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1921 of the RYR2 protein (p.Arg1921Gln).
Color Diagnostics, LLC DBA Color Health	RCV001190715	SCV001358291	uncertain significance	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1921 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/248470 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000182736	SCV002502362	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155110	SCV003844391	uncertain significance	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.5762G>A (p.Arg1921Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248470 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5762G>A has been reported in the literature in individuals who suffered a sudden cardiac death, but with no additional clinical phenotype determined/reported and without strong evidence for causality (Papadakis_2018, Olubando_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia With Sudden Cardiac Death. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.