ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14849A>G (p.Glu4950Gly) (rs1057517873)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414217 SCV000490932 likely pathogenic not provided 2015-04-15 criteria provided, single submitter clinical testing The E4950G variant has not been published asa pathogenic variant or been reported as a benign polymorphism to our knowledge. The E4950G variant was notobserved in approximately 5900 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The E4950G variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that isconserved by class across species. In silico analysis is inconsistent in its predictions as to whether or not thevariant is damaging to the protein structure/function. However, The E4950G variant is located in a pathogenic varianthot spot" region of the RYR2 gene (Medeiros-Domingo et al., 2009). Furthermore, a missense variant in thesame residue (E4950K) and nearby residue (R4959Q) have been reported in the Human Gene MutationDatabase in association with RYR2-related arrhythmia (Stenson et al., 2014), supporting the functionalimportance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is abenign variant cannot be excluded."

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