ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14481C>A (p.Ile4827=) (rs114303476)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619762 SCV000736426 benign Cardiovascular phenotype 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,Synonymous alterations with insufficient evidence to classify as benign
Color RCV000771203 SCV000903199 benign Cardiomyopathy 2018-06-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000036699 SCV000111249 benign not specified 2017-04-12 criteria provided, single submitter clinical testing
GeneDx RCV000036699 SCV000171439 benign not specified 2014-06-03 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.
Integrated Genetics/Laboratory Corporation of America RCV000036699 SCV000920165 benign not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: RYR2 c.14481C>A alters a non-conserved nucleotide resulting in a synonymous change. 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 0.0011 in 277088 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0093 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 155-fold above 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.14481C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "benign." Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000465865 SCV000554589 benign Catecholaminergic polymorphic ventricular tachycardia 2017-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036699 SCV000060354 benign not specified 2015-06-12 criteria provided, single submitter clinical testing p.Ile4827Ile in exon 101 of RYR2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.9% (86/9800) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad; dbSNP rs114303476).

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