ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620350 SCV000736847 uncertain significance Cardiovascular phenotype 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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
Color RCV000771794 SCV000904483 uncertain significance Cardiomyopathy 2018-05-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive with regard to the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study of the corresponding variant in mice (p.Ala1107Met) showed alterations to Ca2+ termination in cultured cells (PMID: 22374134). Crystal structure analysis of the mouse p.Ala1107Met variant has shown destabilization and misfolding within the SPRY2 domain (PMID 25370123). However, clinical relevance of these findings is not clear. This variant has been reported in an individual diagnosed with either strong or possible catecholaminergic polymorphic ventricular tachycardia or atypical long QT syndrome (PMID: 19926015), and in an individual with sudden unexplained death (PMID: 22677073). This variant has been reported to segregate with moderate hypertrophic cardiomyopathy with high penetrance in 5 members from a family (Fujino et al., 2016). However, this variant has also been identified in 118/277072 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This allele frequency is greater than expected for RYR2-related disorders. Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234976 SCV000263115 pathogenic Death in infancy 2015-03-27 no assertion criteria provided clinical testing
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 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1107 of the RYR2 protein (p.Thr1107Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs200236750, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in one individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015) and two cases of sudden unexplained death (PMID: 22677073, 27435932). ClinVar contains an entry for this variant (Variation ID: 43768). One experimental study has shown that this missense change increases the threshold for calcium release termination (PMID: 22374134). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036728 SCV000060383 uncertain significance not specified 2017-08-09 criteria provided, single submitter clinical testing 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 sec ondary finding in an individual with oculocutaneous albinism without mention of cardiac phenotype (Medeiros-Domingo et al 2009, Methner et al. 2016, Stavropolou s et al. 2017, Noboru et al. 2006 (abstract only), LMM data). It has been report ed in ClinVar (Variation ID #43768). In vitro functional studies provide some ev idence that the p.Thr1107Met variant may impact protein function (Tang et al. 20 12). However, these types of assays may not accurately represent biological func tion. This variant has been identified in 79/126600 of European chromosomes by t he genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200236750). Threonine (Thr) at position 1107 is not conserved in mammals or e volutionarily distant species, raising the possibility that a change at this pos ition may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not predicti ve enough to rule out pathogenicity. In summary, due to conflicting data, the cl inical significance of the p.Thr1107Met variant is uncertain.
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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