Submissions for variant NM_001035.3(RYR2):c.8591-8A>G

gnomAD frequency: 0.00004  dbSNP: rs1369273531

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193430	SCV001362241	benign	not specified	2019-06-24	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.8591-8A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 4e-05 in 247150 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.8591-8A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003104017	SCV001689034	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-11-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532889	SCV004360712	benign	Cardiomyopathy	2022-02-25	criteria provided, single submitter	clinical testing