Submissions for variant NM_001035.3(RYR2):c.6440+20C>T

gnomAD frequency: 0.01092  dbSNP: rs115755128

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127837	SCV000171419	benign	not specified	2013-10-29	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001725993	SCV001157530	benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127837	SCV001360983	benign	not specified	2019-08-26	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.6440+20C>T 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. 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 0.0027 in 243510 control chromosomes, predominantly at a frequency of 0.039 within the African or African-American subpopulation in the gnomAD database, including 19 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1559.98 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 African or African-American origin. To our knowledge, no occurrence of c.6440+20C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another likely pathogenic variant has been reported (TTN c.34782_34785delTTGT,p.C11595fs*9- internal sample), providing supporting evidence for a benign role. 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.
Invitae	RCV002514694	SCV002406041	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362769	SCV002657442	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: seen in unaffected individuals, 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.
Clinical Genetics, Academic Medical Center	RCV000127837	SCV001920577	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001725993	SCV001962818	likely benign	not provided		no assertion criteria provided	clinical testing