Submissions for variant NM_001035.3(RYR2):c.4198A>G (p.Ser1400Gly)

gnomAD frequency: 0.01531  dbSNP: rs56229512

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000036743	SCV000050784	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036743	SCV000060398	benign	not specified	2012-02-13	criteria provided, single submitter	clinical testing	Ser1400Gly in exon 32 of RYR2: This variant is classified as benign based on its high frequency in the general population (dbSNP rs56229512; NHLBI Exome Sequenc ing Project, http://evs.gs.washington.edu/EVS). G=157/A=6507 (EA chromosomes, E SP project)
PreventionGenetics, part of Exact Sciences	RCV000036743	SCV000306056	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244245	SCV000318829	benign	Cardiovascular phenotype	2015-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV001093763	SCV000356279	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000356250	SCV000356280	likely benign	Arrhythmogenic right ventricular dysplasia 2	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001093763	SCV000554603	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756605	SCV000884471	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776018	SCV000910577	benign	Cardiomyopathy	2018-03-15	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000756605	SCV000987473	benign	not provided		criteria provided, single submitter	clinical testing
GeneDx	RCV000756605	SCV001945577	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25925909, 33232181)
CeGaT Center for Human Genetics Tuebingen	RCV000756605	SCV002497002	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR2: BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002490497	SCV002802363	likely benign	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-12-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996280	SCV004817727	benign	Catecholaminergic polymorphic ventricular tachycardia	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000756605	SCV005257417	likely benign	not provided		criteria provided, single submitter	not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000036743	SCV000280453	benign	not specified	2015-02-10	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1400Gly in the RYR2 gene. This variant is present in the 1000 Genomes browser with an overall allele frequency of 0.96% (http://browser.1000genomes.org/index.htm). This means that it is present in some 2% of individuals. In some ethnic subgroups the allele frequency is as high as 2-3%. This amino acid location is not conserved across paralog proteins RYR1-RYR3, suggesting that it is not important for channel function (https://cardiodb.org/Paralogue_Annotation/residue.php?gene=RYR2&position=1400). Yano et al. (2006) have reported that disease-causing variants in RYR2 cluster within 3 hotspot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant falls outside of those 3 hotspots. No variation at nearby residues has been reported in HGMD in association with CPVT or ARVC (HGMD professional version as of January 17, 2014). ClinVar lists it as “Benign”, as submitted by Harvard’s Laboratory for Molecular Medicine. As of 2/2/2015 it has been reported in 14/1897 (0.74%) of African American individuals and 178/4126 (4.31%) of Caucasian individuals in the NHLBI Exome Sequencing Project dataset (for overall prevalence of 3.19%; http://evs.gs.washington.edu/EVS/), and two of the Caucasians with the variant were homozygous for it. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs56229512.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000756605	SCV001739734	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036743	SCV001918840	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036743	SCV001927283	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036743	SCV001951913	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036743	SCV001964368	benign	not specified		no assertion criteria provided	clinical testing