ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4198A>G (p.Ser1400Gly) (rs56229512)

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Total submissions: 11
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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, Partners HealthCare 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,PreventionGenetics 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
Illumina Clinical Services Laboratory,Illumina RCV001093763 SCV000356279 benign Catecholaminergic polymorphic ventricular tachycardia type 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 Clinical Services Laboratory,Illumina RCV000356250 SCV000356280 likely benign Arrhythmogenic right ventricular dysplasia, familial, 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.
Invitae RCV000320087 SCV000554603 benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000036743 SCV000884471 benign not specified 2018-11-06 criteria provided, single submitter clinical testing
Color 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
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.

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