Submissions for variant NM_001035.3(RYR2):c.3320C>T (p.Thr1107Met)

gnomAD frequency: 0.00051  dbSNP: rs200236750

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171761	SCV000055283	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036728	SCV000060383	uncertain significance	not specified	2019-01-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Thr1107Met variant in RYR2 has been reported in an individual with CVPT, a case of SIDS, a Japanese family with HCM, an individual with DCM, and as a secondary finding in an individual with oculocutaneous albinism without mention of cardiac phenotype (Medeiros-Domingo et al 2009, Methner et al. 2016, Stavropolous et al. 2017, Noboru et al. 2006 (abstract only), LMM data). It has been reported in ClinVar (Variation ID #43768). In vitro functional studies provide some evidence that the p.Thr1107Met variant may impact protein function (Tang et al. 2012). However, these types of assays may not accurately represent biological function. This variant has been identified in 79/126600 of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200236750). Threonine (Thr) at position 1107 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, due to conflicting data, the clinical significance of the p.Thr1107Met variant is uncertain.
GeneDx	RCV000656971	SCV000235092	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 27538377, 27435932, 22374134, 19926015, 24025405, 20157052, 22677073, 26573135, 25370123, 28404607, 28567303, 30403697, 29396286)
Invitae	RCV000171761	SCV000285720	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620350	SCV000736847	likely benign	Cardiovascular phenotype	2021-06-10	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.
Color Diagnostics, LLC DBA Color Health	RCV000771794	SCV000904483	likely benign	Cardiomyopathy	2019-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036728	SCV001360981	likely benign	not specified	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.3320C>T (p.Thr1107Met) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 & B30.2/SPRY domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249172 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3320C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiopathologies (example: Fujino_2006, Tester_2012, Medeiros-Domingo_2009, Ghazani_2017, Landstrom_2017, Methner_2016, Rangaraju_2018, Roston_2018, Stavropoulos_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.2398+5G>T; CASQ2 IVS5+1G>C (c.606+1G>C); MYH7 c.1447G>A/p.E483K) (Roston_2018, Tester_2012, Internal database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example: Tang_2012). The most pronounced variant effect results in >50%-90% of normal activity. Seven ClinVar submitters have assessed this variant since 2014: three report the variant as likely benign, three as of uncertain significance, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656971	SCV003799224	likely benign	not provided	2022-04-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656971	SCV003820601	likely benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656971	SCV004184031	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	RYR2: BP4
PreventionGenetics, part of Exact Sciences	RCV003952421	SCV004769434	likely benign	RYR2-related condition	2023-09-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234976	SCV000263115	pathogenic	Death in infancy	2015-03-27	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000656971	SCV000924928	uncertain significance	not provided	2018-02-02	no assertion criteria provided	provider interpretation