Submissions for variant NM_001035.3(RYR2):c.385-9A>C

dbSNP: rs140998248

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425970	SCV000514430	benign	not specified	2016-04-07	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.
Eurofins Ntd Llc (ga)	RCV000425970	SCV000704536	likely benign	not specified	2017-01-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000425970	SCV000710923	likely benign	not specified	2016-05-02	criteria provided, single submitter	clinical testing	c.385-9A>C in intron 6 of RYR2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (20/6896) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs140998248).
Invitae	RCV002524791	SCV000760704	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000425970	SCV000918171	benign	not specified	2018-07-16	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.385-9A>C 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 was observed with an allele frequency of 0.00027 in 271504 control chromosomes (gnomAD), predominantly in Africans, 62/23486 chromosomes (allele frequency 0.0026). The observed variant frequency within African control individuals in the gnomAD database is approximately 43-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.385-9A>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171010	SCV001333679	benign	Cardiomyopathy	2018-06-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171010	SCV001354748	benign	Cardiomyopathy	2018-11-27	criteria provided, single submitter	clinical testing