Submissions for variant NM_001035.3(RYR2):c.815G>T (p.Arg272Leu)

gnomAD frequency: 0.00005  dbSNP: rs377368967

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618097	SCV000737790	uncertain significance	Cardiovascular phenotype	2022-01-07	criteria provided, single submitter	clinical testing	The p.R272L variant (also known as c.815G>T), located in coding exon 11 of the RYR2 gene, results from a G to T substitution at nucleotide position 815. The arginine at codon 272 is replaced by leucine, an amino acid with dissimilar properties. 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.
Invitae	RCV001100222	SCV000815043	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-03-21	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with RYR2-related conditions. 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 519353). This variant is present in population databases (rs377368967, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 272 of the RYR2 protein (p.Arg272Leu).
Color Diagnostics, LLC DBA Color Health	RCV000772651	SCV000905910	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This variant is located in 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 been identified in 11/280472 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.
Illumina Laboratory Services, Illumina	RCV001100221	SCV001256731	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001100222	SCV001256732	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249072	SCV001423021	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Arg272Leu variant in RYR2 has not been previously reported in individuals with RYR2-related diseases but has been identified in 0.007793% (10/128322) of European (non-Finnish) chromosomes and 0.004133% (1/24196) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377368967). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS in ClinVar (Variation ID: 519353). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg272His, has been reported as a VUS in association with disease in ClinVar (Variation ID: 618352). The number of missense variants reported in RYR2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2, PP3 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV002491324	SCV002793194	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-29	criteria provided, single submitter	clinical testing