Submissions for variant NM_001035.3(RYR2):c.4596+12G>A

gnomAD frequency: 0.00153  dbSNP: rs148557427

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036745	SCV000060400	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	c.4596+12G>A in Intron 34 of RYR2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 0.5% (17/3368) of African American chromosomes from a br oad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS; dbSNP rs148557427).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000036745	SCV001158252	likely benign	not specified	2019-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036745	SCV001437281	benign	not specified	2020-09-08	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4596+12G>A 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 0.00058 in 262302 control chromosomes, predominantly at a frequency of 0.006 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 175 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.4596+12G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001528786	SCV001851780	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Invitae	RCV003105780	SCV002358441	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-29	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528786	SCV001741136	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036745	SCV001922207	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528786	SCV001926254	likely benign	not provided		no assertion criteria provided	clinical testing