ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4596+12G>A (rs148557427)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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
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

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