Submissions for variant NM_001035.3(RYR2):c.4445G>A (p.Arg1482His)

gnomAD frequency: 0.00016  dbSNP: rs373024059

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171763	SCV000050703	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171763	SCV000235103	likely benign	not provided	2020-02-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported with conflicting interpretations of pathogenicity by other clinical laboratories in ClinVar (ClinVar Variant ID# 191544; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not 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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212979	SCV000272388	likely benign	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV001100766	SCV000541696	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773225	SCV000906837	likely benign	Cardiomyopathy	2018-04-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098955	SCV001255357	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001100766	SCV001257302	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212979	SCV002074373	likely benign	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4445G>A (p.Arg1482His) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 240782 control chromosomes (gnomAD). The observed variant frequency is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.4445G>A has been reported in the literature in at least one individual affected with CPVT and at least one individual affected with Brugada syndrome, however without strong evidence for causality in both cases (e.g., Landstrom_2017, Seidelmann_2017). Additionally, c.4445G>A has been reported as a "likely not pathogenic" variant in the settings of exome sequencing in the ClinSeq cohort not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (example, Ng_2013). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 28404607, 28087566). Seven ClinVar submitters (evaluation after 2014) have cited the variant; 6 submitters classified the variant as likely benign and one submitter classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002326941	SCV002629132	likely benign	Cardiovascular phenotype	2018-06-30	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.