Submissions for variant NM_001035.3(RYR2):c.2301G>T (p.Ser767=)

gnomAD frequency: 0.00150  dbSNP: rs117588730

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079378	SCV000111250	benign	not specified	2013-09-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000079378	SCV000171407	benign	not specified	2013-10-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079378	SCV000204494	benign	not specified	2013-10-21	criteria provided, single submitter	clinical testing	Ser767Ser in exon 21 of RYR2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.6% (15/572) of Asi an chromosomes by the 1000 Genomes Project (dbSNP rs117588730). Ser767Ser in ex on 21 of RYR2 (rs117588730; allele frequency = 2.6%, 15/572)
Invitae	RCV001093913	SCV000285712	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079378	SCV000306048	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001093913	SCV000356245	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	RCV000383237	SCV000356246	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588457	SCV000697614	benign	not provided	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.2301G>T (p.Ser767Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 306/120764 control chromosomes (7 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0344308 (297/8626). This frequency is about 1377 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), strong evidence that this is a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Ambry Genetics	RCV000618616	SCV000734911	benign	Cardiovascular phenotype	2016-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769776	SCV000901201	benign	Cardiomyopathy	2016-04-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769776	SCV000910756	benign	Cardiomyopathy	2018-03-15	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079378	SCV001921977	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079378	SCV001956334	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079378	SCV001974608	benign	not specified		no assertion criteria provided	clinical testing