ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3320C>T (p.Thr1107Met) (rs200236750)

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Total submissions: 9
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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 type 1 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare 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 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing The T1107M variant in the RYR2 gene has been reported in individuals with various cardiac phenotypes (Fujino et al., 2006; Medeiros-Domingo et al., 2009; Tester et al., 2012; Methner et al., 2016). Fujino et al. (2006) observed this variant in an individual with HCM and it segregated with disease in four relatives; of note, these data have not been published in a peer-reviewed journal. Medeiros-Domingo et al. (2009) identified T1107M in an individual from a cohort with either strong or possible CPVT diagnoses; however, no specific clinical or segregation information was provided for this case. The variant was also reported in a 13 year-old female with sudden unexplained death (SUD) and history of syncope who also harbored a variant in the KCNH2 gene (Tester et al., 2012). Methner et al. (2016) identified the T1107M variant in a 5 month-old male with sudden infant death syndrome (SIDS) who also harbored variants in the KCNH2 and SCN5A genes. The T1107M variant has also been observed in multiple other unrelated individuals referred for cardiomyopathy and/or arrhythmia genetic testing at GeneDx. This variant is observed in 26/30,782 alleles from individuals of South Asian ancestry and 79/126,600 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The T1107M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Expression studies of the corresponding RYR2 variant in mice (A1107M) showed alterations to Ca2+ termination in HEK293 cells (Tang et al., 2012), and crystal structure analysis of the mouse A1107M variant demonstrated both destabilization and misfolding within the SPRY2 domain (Lau et al., 2014). However, it is not clear whether these effects would be sufficient to cause disease in humans. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, T1107M is 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). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000228614 SCV000285720 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620350 SCV000736847 uncertain significance Cardiovascular phenotype 2019-02-23 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000771794 SCV000904483 likely benign Cardiomyopathy 2019-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036728 SCV001360981 uncertain significance not specified 2019-01-29 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 and 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 0.00043 in 277072 control chromosomes (gnomAD). The observed variant frequency is approximately 7 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 benign. c.3320C>T has been reported in the literature in individuals with various phenotype, including HCM, CPVT, sudden death, lung cancer, oculocutaneous albinism type 1 (Rangaraju_2018, Roston_2018, Landstrom_2017, Methner_2016, Tester_2012, Medeiros-Domingo_2009, Fujino_2006). 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)) (Roston_2018, Tester_2012), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a cell line expressing the mouse RyR2 A1107M variant (which corresponds to the human RyR2 T1107M variant) demonstrated the variant increases the threshold for Ca2+ release termination and decreases the fractional Ca2+ release; however the clinical significance of these findings is unknown. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (4x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
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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