ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.349C>T (p.His117Tyr) (rs1057524592)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439111 SCV000535990 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The H117Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H117Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, H117Y is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Nevertheless, this variant has not been observed in a significant number of affected individuals, and there are no functional or segregation studies available to further clarify the role of this variant in disease.
Invitae RCV001056192 SCV001220619 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-04-11 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 117 of the RYR2 protein (p.His117Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 392683). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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