ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1548T>C (p.Asp516=) (rs146129084)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036706 SCV000060361 likely benign not specified 2015-03-06 criteria provided, single submitter clinical testing p.Asp516Asp in exon 16 of RYR2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (51/66652) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro; dbSNP rs146129084).
GeneDx RCV000036706 SCV000171405 benign not specified 2014-05-05 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.
Invitae RCV000468470 SCV000554621 likely benign not provided 2019-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618567 SCV000736840 likely benign Cardiovascular phenotype 2017-05-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign,In silico models in agreement (benign)
Color RCV000771845 SCV000904559 benign Cardiomyopathy 2018-10-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036706 SCV000918168 benign not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: RYR2 c.1548T>C 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 0.00045 in 276574 control chromosomes (gnomAD). The observed variant frequency is approximately 7.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1548T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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