ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8162T>C (p.Ile2721Thr) (rs201500134)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000036794 SCV000605050 uncertain significance not specified 2016-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621651 SCV000734924 likely benign Cardiovascular phenotype 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000590879 SCV000700103 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color RCV000771869 SCV000904592 uncertain significance Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with RYR2-related cardiovascular disorders in the literature. This variant is fairly common in the general population and has been identified in 84/68536 non-Finnish European chromosomes (0.1225%) by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
GeneDx RCV000036794 SCV000235152 uncertain significance not specified 2016-09-28 criteria provided, single submitter clinical testing The I2721T variant of uncertain significance in the RYR2 gene has been previously reported intwo individuals (van Spaendonck-Zwarts et al., 2014; Hertz et al., 2015). This variant was initiallyreported as a variant of uncertain significance in one individual with atrial fibrillation and dilatedcardiomyopathy who was found to harbor additional variants of uncertain significance in theDMD and TTN genes (van Spaendonck-Zwarts et al., 2014). Subsequently, Hertz et al. (2015)reported I2721T in an individual diagnosed with Long QT syndrome at 19 years of age; however,she was also found to harbor a KCNH2 variant classified as likely pathogenic. This variant hasalso been identified independently and in conjunction with additional cardiogenetic variants inindividuals referred for arrhythmia and cardiomyopathy genetic testing at GeneDx; however, thusfar, segregation data is limited or absent for these individuals due to the lack of clinical informationprovided and/or insufficient participation by informative family members. Additionally, theI2721T variant is classified in ClinVar as a variant of uncertain significance by two clinicallaboratories (ClinVar SCV000060449.4; SCV000285751.1; Landrum et al., 2016). The I2721Tvariant was not observed with any significant frequency in approximately 5,800 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project. Although thissubstitution occurs at a position where amino acids with similar properties to Isoleucine aretolerated across species, the I2721T variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/orother properties. Consequently, in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nevertheless, the I2721T variant is not located in one of the threehot-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 ispathogenic or rare benign.
Invitae RCV000227013 SCV000285751 likely benign Catecholaminergic polymorphic ventricular tachycardia 2018-01-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036794 SCV000060449 uncertain significance not specified 2012-09-21 criteria provided, single submitter clinical testing The Ile2721Thr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 4/7968 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. Additional inform ation is needed to fully assess the clinical significance of this variant.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656198 SCV000678392 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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