ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12544G>C (p.Glu4182Gln) (rs397516508)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182821 SCV000235207 likely pathogenic not provided 2013-12-27 criteria provided, single submitter clinical testing p.Glu4182Gln (GAG>CAG): c.12544 G>C in exon 90 of the RYR2 gene (NM_001035.2). The Glu4182Gln variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Glu4182Gln variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. However, the Glu4182Gln residue is conserved across species. In silico analysis predicts Glu4182Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Asn4178Tyr, Asn4178Ser, Glu4187Gln, and Leu4188Pro) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. Glu4182Gln is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros- Domingo A et al., 2009). Furthermore, the Glu4182Gln variant 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. In summary, while Glu4182Gln is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in CPVT panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036672 SCV000060327 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2013-04-26 criteria provided, single submitter clinical testing The Glu4182Gln variant in RYR2 has been identified by our laboratory in 1 Caucas ian child with CPVT, where it occurred de novo. This variant has not been seen i n large population studies. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu4182Gln variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, all available data supports that the Glu4182Gln variant is likely pathogenic, but additional studies are needed to fu lly assess its clinical significance.

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