ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1298T>C (p.Leu433Pro) (rs121918602)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151756 SCV000200139 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2015-02-04 criteria provided, single submitter clinical testing The p.Leu433Pro variant in RYR2 has been reported in 1 individual with ventricul ar arrhythmia, 1 individual with arrhythmogenic right ventricular dysplasia type 2 (ARVD2) and segregated with ARVD2 in 4 affected relatives from 1 family (Tiso 2001, Steriotis 2012). It has also been identified by our laboratory in 1 indiv idual with polymorphic ventricular bigeminy as well as in 2 family members with CPVT, 1 family member with history of cardiac arrest, and was absent in 6 unaffe cted relatives who were much older than the typical age of onset for CPVT. This variant was absent from large population studies and is listed in dbSNP without frequency information (rs121918602). Both in-vitro and in-vivo functional studie s have shown that the p.Leu433Pro variant impacts protein function (Thomas 2004, Jiang 2005, Tang 2012, and Shan 2012); however, these assays may not accurately represent biological function. In summary, this variant meets our criteria to b e classified as pathogenic for CPVT in an autosomal dominant manner (http://www. partners.org/personalizedmedicine/LMM) based upon segregation studies and absenc e from controls.
Integrated Genetics/Laboratory Corporation of America RCV000780694 SCV000918174 pathogenic Cardiovascular phenotype 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.1298T>C (p.Leu433Pro) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found to be associated with reduced luminal Ca threshold at which Ca release terminates, desensitized caffeine-induced activation in HEK293 cells, increased diastolic SR Ca2+ leak in atrial myocytes (Tang_2012, Thomas_2004), and 37% AF occurrence in an in-vivo mouse model (Shan_2012). This variant is absent in 269324 control chromosomes in gnomAD and Tiso_2001. This variant was reported in multiple patients with ARVD (in a family where it segregated with disease)(Tiso_2001), CPVT, and LQTS (Steriotis_2012, Shigemizu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000013825 SCV000034072 pathogenic Arrhythmogenic right ventricular dysplasia, familial, 2 2001-02-01 no assertion criteria provided literature only
Medical Research Institute,Tokyo Medical and Dental University RCV000190229 SCV000222080 uncertain significance Long QT syndrome no assertion criteria provided research

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