Submissions for variant NM_001035.3(RYR2):c.3026G>A (p.Arg1009Gln)

gnomAD frequency: 0.00001  dbSNP: rs754812132

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003103772	SCV000541715	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1009 of the RYR2 protein (p.Arg1009Gln). This variant is present in population databases (rs754812132, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 404229). 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. 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	RCV001181369	SCV001346502	uncertain significance	Cardiomyopathy	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1009 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). 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 8/280576 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.
GeneDx	RCV000786202	SCV001795756	uncertain significance	not provided	2020-09-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 404229; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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)
Fulgent Genetics, Fulgent Genetics	RCV002489000	SCV002785018	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-12-05	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786202	SCV000924918	uncertain significance	not provided	2016-10-03	no assertion criteria provided	provider interpretation	p.Arg1009Gln in the RYR2 gene We have seen this variant in one person with DCM and SCA. Testing was sent to Invitae. Given the lack of case data we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature as of 10/2016. Per the Invitae report, "This sequence change replaces arginine with glutamine at codon 1009 of the RYR2 protein (p.Arg1009Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine." The report also notes that the variant is predicted to be disruptive by in silico splicing and protein structure and function algorithms, but no functional data is available to confirm this. The Paralogue Annotation tool at cardiodb.org reports that no paralogue variants have been mapped to corresponding residues in related transcripts. The classification listed there is putative benign. The Arg1009Gln variant was reported online in 3 of 60,232 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 10/3/2016). Specifically, the variant was observed in 2 of 5,767 Latino people (AF: 0.017%) and 1 of 4,893 African people (AF: 0.01%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). A different variant affecting the same codon, Arg1009Trp, which was reported online in 7 of 60,232 individuals in ExAC (as of 10/3/2016). Specifically, the variant was observed in 2 of 5,768 Latino people (AF: 0.017%), 1 of 4,313 East Asian people (AF: 0.017%), 1 of 8,213 South Asian people, and 3 of 33,306 non-Finnish European people.