ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs749032742
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2020-09-23 criteria provided, single submitter clinical testing Reported in association with sudden unexplained death (SUD) in one patient who harbored additional variants in other genes (Sanchez et al., 2016), and reported as homozygous in an unrelated patient with acute viral myocarditis at one month of age who had supraventricular tachycardia on ECG (Belkaya et al., 2017); 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); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID 427953; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27930701, 28359509)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769774 SCV000901197 uncertain significance Cardiomyopathy 2017-10-02 criteria provided, single submitter clinical testing
Invitae RCV002526064 SCV000960420 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-29 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000769774 SCV001357914 uncertain significance Cardiomyopathy 2022-12-07 criteria provided, single submitter clinical testing This variant replaces histidine with glutamine at codon 464 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 27930701) and in a homozygous pediatric patient with acute myocarditis and supraventricular tachycardia (PMID: 28359509). This variant has been identified in 13/248638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002489201 SCV002785452 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-09-03 criteria provided, single submitter clinical testing

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