ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1392C>A (p.His464Gln) (rs749032742)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769774 SCV000901197 uncertain significance Cardiomyopathy 2017-10-02 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000498149 SCV000579539 uncertain significance Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score unknown significance
GeneDx RCV000522514 SCV000616986 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The H464Q variant has been reported in association with sudden unexplained death (SUD) in one patient (Sanchez et al., 2016) This variant was also reported as a homozygous variant in a patient with acute viral myocarditis at one month of age and had supraventricular tachycardia on ECG (Belkaya et al., 2017). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The H464Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The H464Q variant 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). However, this substitution occurs at a position that is only conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000819743 SCV000960420 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 464 of the RYR2 protein (p.His464Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs749032742, ExAC 0.02%). This variant has been observed in an individual who suffered a sudden unexplained death (PMID: 28166282) and in a homozygous individual affected with acute viral myocarditis (PMID: 28359509). ClinVar contains an entry for this variant (Variation ID: 427953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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