ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.385-9A>C (rs140998248)

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Total submissions: 7
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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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000425970 SCV000704536 likely benign not specified 2017-01-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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,; db SNP rs140998248).
Invitae RCV000639140 SCV000760704 benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 RCV001171010 SCV001354748 benign Cardiomyopathy 2018-11-27 criteria provided, single submitter clinical testing

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