ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.7202G>A (p.Arg2401His) (rs794728756)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182760 SCV000235145 likely pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing The R2401H likely pathogenic variant in the RYR2 gene has been reported in multiple individuals with a clinical history indicative of CPVT (Aizawa et al, 2005; Medeiros-Domingo et al., 2009; Roux-Buisson et al., 2011; Tester et al., 2011). More specifically, three children, under ten years of age, have been reported with this variant and recurrent stress-induced syncope/sudden cardiac arrest and/or an abnormal stress test, noteworthy for premature ventricular contractions (Aizawa et al, 2005; Roux-Buisson et al., 2011; Tester et al., 2011). Significantly, both parents of one child with exercise-induced sudden cardiac arrest did not harbor the variant, suggesting de novo occurrence (Tester et al., 2011). Roux-Buisson et al. (2011) discovered that R2401H was inherited from an asymptomatic mother, albeit she was mosaic for the variant which likely explains her lack of symptoms. A young sibling to this index case notably died suddenly during physical exertion; a sample was not available for testing (Roux-Buisson et al., 2011). Furthermore, multiple individuals referred for CPVT genetic testing at GeneDx were found to harbor this variant, in the absence of any other disease-causing variants, and these referrals were for young children similarly affected to those published in the literature. The R2401H variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. Although R2401H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, in silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, R2401H is classified in ClinVar as a likely pathogenic variant in association with CPVT by one additional clinical laboratory (ClinVar SCV000264186.1; Landrum et al., 2016).Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Blueprint Genetics RCV000208074 SCV000264186 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2015-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247473 SCV000318695 likely pathogenic Cardiovascular phenotype 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification

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