Submissions for variant NM_001035.3(RYR2):c.2267G>A (p.Ser756Asn)

gnomAD frequency: 0.00016  dbSNP: rs193922623

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036714	SCV000060369	likely benign	not specified	2018-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000786207	SCV000235075	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Reported in association with HCM, DCM, and sudden unexplained death (Lopes et al., 2015; Subbotina et al., 2019; Burstein et al., 2021); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30878466, 19926015, 28404607, 32746448, 25351510)
Ambry Genetics	RCV000242970	SCV000319504	likely benign	Cardiovascular phenotype	2019-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV001093912	SCV000356243	likely benign	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 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.
Illumina Laboratory Services, Illumina	RCV000287643	SCV000356244	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.
Invitae	RCV001093912	SCV000541700	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036714	SCV000697613	uncertain significance	not specified	2017-06-19	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.2267G>A (p.Ser756Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict damaging outcome for this variant. This variant was found in 24/120700 control chromosomes from ExAC at a frequency of 0.0001988, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, this variant has been detected at an allele frequency of ~0.5% (47/10152 chromosomes) in Ashkenazi subpopulation in gnomAD database, further supporting benign outcome. However, five clinical diagnostic laboratories (via ClinVar) have classified this variant as uncertain significance. LMM (via ClinVar) has reported this variant in two Caucasian adults with DCM and one Ashkenazi Jewish adult with HCM and has classified the variant as a VUS, although they do not report if this variant was found with other pathogenic variants in other genes, do not provide any familial co-segregation analysis and have not used ExAC data at that time. Due to the possibility of low penetrance pathogenic variants in the control population and unknown status of cardiological information in control populations, possibility of digenic inheritance in arrythmias and due to lack of functional and clinical data for this variant, the variant has been classified as a VUS-possibly benign until additional evidence becomes available.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000036714	SCV000747970	uncertain significance	not specified	2017-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181067	SCV001346132	likely benign	Cardiomyopathy	2018-10-22	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157446	SCV000207190	likely pathogenic	Ventricular fibrillation, paroxysmal familial, type 1	2014-03-20	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786207	SCV000924927	uncertain significance	not provided	2017-11-01	no assertion criteria provided	provider interpretation	p.Ser756Asn (c.2267G>A) in the RYR2 gene (NM_001035.2; chr1-237664074-G-A) SCICD Classification: variant of uncertain significance, likely benign based on limited data to associate this gene with disease and relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: RYR2 has not been associated with HCM Region-level evidence: Per the lab report, this variant is not in one of the regions of RYR2 that is enriched for pathogenic variation. Population data: Highest MAF in Ashkenazi Jewish population: 0.4630%. The variant was reported online in 56 of 138571 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000786207	SCV001978203	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000786207	SCV001978554	likely benign	not provided		no assertion criteria provided	clinical testing