Submissions for variant NM_001035.3(RYR2):c.1454G>A (p.Arg485Gln)

gnomAD frequency: 0.00008  dbSNP: rs752144775

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182863	SCV000235251	uncertain significance	not specified	2015-09-10	criteria provided, single submitter	clinical testing	This missense change is denoted Arg485Gln (aka R485Q) at the protein level and c.1454 G>A at the cDNA level. The Arg485Gln variant in the RYR2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg485Gln results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a residue that is conserved across species. The Arg485Gln variant was not detected in up 400 alleles from control individuals of Caucasian ancestry tested at GeneDx, indicating it is not a common benign variant in this population. However, the Arg485Gln is not located in one of the three mutation hot spots in the RYR2 gene (Medeiros-Domingo, et al. 2009). With the clinical and molecular information available at this time, we cannot unequivocally determine whether the Arg485Gln variant in the RYR2 gene is a disease-causing mutation or a rare benignvariant. The variant is found in CPVT panel(s).
Blueprint Genetics	RCV000208338	SCV000264179	uncertain significance	Ventricular tachycardia	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV002515340	SCV000541669	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-11-01	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 485 of the RYR2 protein (p.Arg485Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 30403697, 34088380). ClinVar contains an entry for this variant (Variation ID: 201374). 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. 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	RCV000777944	SCV000914042	uncertain significance	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 485 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 not been identified 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000777944	SCV000995096	uncertain significance	Cardiomyopathy	2019-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777944	SCV001333882	uncertain significance	Cardiomyopathy	2019-01-08	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223808	SCV002503393	uncertain significance	not provided	2020-06-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390467	SCV002698227	uncertain significance	Cardiovascular phenotype	2023-05-26	criteria provided, single submitter	clinical testing	The p.R485Q variant (also known as c.1454G>A), located in coding exon 15 of the RYR2 gene, results from a G to A substitution at nucleotide position 1454. The arginine at codon 485 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in an individual from a hypertrophic cardiomyopathy cohort who also had variants in other cardiac related genes, including an MYBPC3 splice site mutation (Bottillo I et al. Gene. 2016;577:227-35). This variant was also detected in a cohort referred for exome sequencing and a left ventricular non-compaction (LVNC) cohort (Landstrom AP et al. Circ Arrhythm Electrophysiol. 2017;10:e004742; Richard P et al. Clin Genet, 2019 03;95:356-367). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.