ClinVar Miner

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

gnomAD frequency: 0.00051  dbSNP: rs200236750
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Total submissions: 13
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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 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,; 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: 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.
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 2024-03-01 criteria provided, single submitter clinical testing RYR2: BP4
PreventionGenetics, part of Exact Sciences RCV004541106 SCV004769434 likely benign RYR2-related disorder 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

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