ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1250G>T (p.Arg417Leu) (rs751428303)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182679 SCV000235058 likely pathogenic not provided 2013-06-04 criteria provided, single submitter clinical testing p.Arg417Leu (CGA>CTA): c.1250 G>T in exon 14 of the RYR2 gene (NM_001035.2). The Arg417Leu variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg417Leu results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Leucine at a position that is conserved across species. In silico analysis predicts Arg417Leu is probably damaging to the protein structure/function. Arg417Leu is located in the N-terminal mutation hot spot" domain, and mutations in nearby residues (Arg414Cys, Arg414Leu, Thr415Arg, Ile419Phe) have been reported in association with CPVT, further supporting the functional importance of this region of the protein (Medeiros-Domingo A et al., 2009). Furthermore, Arg417Leu was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Arg417Leu is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s)."

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