Submissions for variant NM_001035.3(RYR2):c.4597-11del

dbSNP: rs3841805

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036747	SCV000060402	benign	not specified	2012-08-07	criteria provided, single submitter	clinical testing	4597-11delA variant in intron 34 of RYR2: This variant has been identified in 12 .8% (25/572) of Asian chromosomes from a broad population by the 1000 Genomes pr oject (dbSNP rs3841805).
GeneDx	RCV000036747	SCV000234999	benign	not specified	2014-05-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV000036747	SCV000306059	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000331784	SCV000356285	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000386363	SCV000356286	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776060	SCV000910708	benign	Cardiomyopathy	2018-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036747	SCV001338399	benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4597-11delA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0053 in 244908 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 89 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4597-11delA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529435	SCV001472600	benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV002513422	SCV002480922	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336124	SCV002637554	benign	Cardiovascular phenotype	2014-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529435	SCV001742896	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036747	SCV001925902	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036747	SCV001929206	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036747	SCV001970610	benign	not specified		no assertion criteria provided	clinical testing