Submissions for variant NM_001035.3(RYR2):c.3380A>G (p.Glu1127Gly)

gnomAD frequency: 0.00048  dbSNP: rs200525962

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171762	SCV000055284	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036729	SCV000060384	likely benign	not specified	2015-04-15	criteria provided, single submitter	clinical testing	p.Glu1127Gly in exon 28 of RYR2: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (92/16512) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs200525962).
GeneDx	RCV000171762	SCV000235094	benign	not provided	2019-09-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 23861362, 25650408, 26656175, 27930701, 28404607, 29350269, 33825858)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001098854	SCV000554622	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171762	SCV000697621	likely benign	not provided	2017-05-30	criteria provided, single submitter	clinical testing	Variant summary: : The RYR2 c.3380A>G (p.Glu1127Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 136/120770 control chromosomes (including 4 homozygotes) from ExAC at a frequency of 0.0011261, which is approximately 20 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. It is more common in South Asian subpopulation with an allele frequency of 0.0055 (92/16512 chromosomes). This variant has been found in two patients (one with HCM and another with Brugada syndrome) without strong evidence for causality (Bottillo_2015, Le Scouarnec_2015). The HCM patient with this variant also carried another VUS MYBPC3 p.M555T. In ClinVar while three clinical laboratories have classified this variant as likely benign/benign, other three have classified it as VUS; all without evidence for independent evaluation. This variant is also located outside of mutational "hotspots" region (exons 1-16) (Medeiros-Domingo, A et al., 2009; PMID: 19926015). Taken together, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769783	SCV000901208	uncertain significance	Cardiomyopathy	2016-06-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769783	SCV000902956	likely benign	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845327	SCV000987373	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098853	SCV001255247	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-02-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098854	SCV001255248	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-02-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293091	SCV001434074	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171762	SCV001471097	likely benign	not provided	2020-05-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171762	SCV002585194	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RYR2: BS2
Ambry Genetics	RCV002453307	SCV002618211	likely benign	Cardiovascular phenotype	2021-12-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001098854	SCV002767435	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM and PMID: 22787013). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of catecholaminergic polymorphic ventricular tachycardia, 1 (MIM#604772). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SPRY domain 2 (NCBI, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported as a VUS, but more recently as likely benign or benign (LOVD, ClinVar, Cardiodb). It has also been observed in several individuals with sudden unexplained death, hypertrophic cardiomyopathy or catecholaminergic polymorphic ventricular tachycardia (PMID: 28404607, PMID: 29350269, PMID: 27054166). (I) 1206 - This variant has been shown to be paternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Blueprint Genetics	RCV000157454	SCV000207198	uncertain significance	Sudden cardiac death	2014-05-14	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000171762	SCV000280450	likely benign	not provided	2017-03-20	no assertion criteria provided	provider interpretation	UPDATE on 3/20/2017: gnomAD shows this variant to have an allele frequency of 0.55% in South Asians, including 5 homozygotes, and to be present in 275 individuals out of the 140,000 in gnomAD total.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254751	SCV001430840	benign	Sudden unexplained death	2019-11-28	no assertion criteria provided	research	The RYR2 Glu1127Gly has been identified previously in individuals with a broad range of cardiac conditions. The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.001 which is higher then expected for inherited cardiac disease. In summary, based on the high allele frequency in the general population we classify RYR2 Glu1127Gly as "benign".