ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2629C>T (p.His877Tyr) (rs372575878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619081 SCV000737831 uncertain significance Cardiovascular phenotype 2016-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000182701 SCV000235080 uncertain significance not provided 2014-07-02 criteria provided, single submitter clinical testing p.His877Tyr (CAT>TAT): c.2629 C>T in exon 23 of the RYR2 gene (NM_001035.2). The H877Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H877Y variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The H877Y 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. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, the H877Y variant is not located in any of the mutation hot spot" regions in the RYR2 gene (Medeiros-Domingo A et al., 2009), and no mutations in nearby residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY,ARVC panel(s)."
Invitae RCV000639124 SCV000760686 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 877 of the RYR2 protein (p.His877Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs372575878, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201231). 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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