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

gnomAD frequency: 0.00001  dbSNP: rs749032742

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526064	SCV000960420	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-22	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
All of Us Research Program, National Institutes of Health	RCV004003435	SCV004845602	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-06	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.
Ambry Genetics	RCV004023275	SCV005037059	likely benign	Cardiovascular phenotype	2023-11-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.