Submissions for variant NM_001035.3(RYR2):c.13291G>A (p.Glu4431Lys)

gnomAD frequency: 0.00028  dbSNP: rs571985775

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151775	SCV000200200	uncertain significance	not specified	2018-11-16	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: All ClinVar submissions are recent (2017). HGMD: 3 more publica tions which will probably not increase the classification. ClinVar: VUS by sever al labs (all recent, 2017)
GeneDx	RCV000766733	SCV000235219	uncertain significance	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Initially reported in one Norwegian individual with a history of syncope and a prolonged QT interval (Berge et al., 2008), and was later also described in a 25-year-old male with autopsy-negative sudden unexplained death who had a history of palpitations and negative family history (Wang et al., 2014).; Reported in a patient with short QT syndrome (SQTS) in the published literature who harbored additional cardiogenetic variants (Schneider et al., 2021); 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 supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24631775, 24025405, 27538377, 26633542, 19926015, 28404607, 23022705, 19362677, 27535533, 18752142, 34712558)
Invitae	RCV000578054	SCV000541718	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-03	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000577997	SCV000679818	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578054	SCV000679819	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000577938	SCV000679820	uncertain significance	Left ventricular noncompaction	2017-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620731	SCV000735762	likely benign	Cardiovascular phenotype	2021-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Ambry Genetics	RCV000622853	SCV000742577	uncertain significance	Inborn genetic diseases	2016-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777878	SCV000913886	uncertain significance	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 4431 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 18752142), sudden unexplained death (PMID: 24631775), and early-onset atrial fibrillation (PMID: 31638414). This variant has also been identified in 54/242862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for RYR2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151775	SCV000918175	uncertain significance	not specified	2017-12-26	criteria provided, single submitter	clinical testing	Variant summary: The c.13291G>A (p.Glu4431Lys) in RYR2 gene is a missense variant involves a mildly conserved nucleotide located within Ryanodine Receptor TM 4-6 domain (InterPro). The 3/4 in silico tools used predict benign outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.13291G>A was identified in the control population dataset of gnomAD at a low frequency of 0.00021 (51/ 239208 chrs tested), predominantly in individuals of European (N-F) descent (0.0004684; 49/104610). The observed frequency significantly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00003, although arrhythmic phenotype in these individuals cannot be ruled out. The variant has been reported in at least three individuals with clinical findings suggestive of arrhythmia and or CPVT, however without strong evidence for causality (eg. segregation, co-occurrence information was not provided). Multiple diagnostic centers have classified the variant as VUS. Taking all evidence into consideration, the variant was classified as VUS-possibly benign, until new information becomes available.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852418	SCV000995102	uncertain significance	Hypertrophic cardiomyopathy	2017-07-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000577997	SCV001252608	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-11-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000578054	SCV001252609	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-11-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000766733	SCV002048212	uncertain significance	not provided	2020-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766733	SCV002544388	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	RYR2: PM1
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000151775	SCV000280443	uncertain significance	not specified	2015-09-17	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu4431Lys (E4431K; c.13291 G>A) in the RYR2 gene: Based on the limited data available about this variant (reviewed below), we consider this a variant of unknown significance (VUS). Most reported disease-causing variants in this gene are missense variants associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) according to HGMD. The RYR2 gene is also associated, rarely, with arrhythmogenic right ventricular cardiomyopathy (ARVC) type 2. However, this variant has not been reported in a patient with CPVT or ARVC, and instead has been reported in one individual with a history of prolonged QTc and syncope (Berge et al. 2008), in one individual with HCM and polymorphic VT who also carried a pathogenic variant for HCM in another gene (Kellen 2012-abstract), and in a 25-year-old Caucasian male with autopsy-negative sudden cardiac death and a history of palpitations but no family history (Wang et al. 2014). Yano et al. (2006) reported that disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant does fall within the C-terminal disease-causing hotspot. This is a non-conservative amino acid substitution from a negatively-charged glutamic acid to a positively-charged lysine at a residue that is conserved across vertebrate species. This glutamic acid is not conserved across paralog proteins (RYR1-RYR3) according to cardiodb: (http://cardiodb.org/Paralogue_Annotation/residue.php?gene=RYR2&position=4431). In silico analysis with PolyPhen-2 predicts this variant to be “benign” with a score of 0.09. There are no missense variants at nearby residues (+/-10) listed in HGMD in association with disease (as of January, 2014). The variant has not been seen in ~6000 individuals from published controls and publicly available population datasets. Berge et al. (2008) did not detect it in 94 controls. It is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1800 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this codon listed in 1000 Genomes (as of November 3, 2014).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766733	SCV001743953	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766733	SCV001955362	uncertain significance	not provided		no assertion criteria provided	clinical testing