ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4734C>T (p.Pro1578=) (rs201880756)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620163 SCV000736197 benign Cardiovascular phenotype 2015-07-21 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
Color RCV000771249 SCV000903351 benign Cardiomyopathy 2018-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000036755 SCV000514445 benign not specified 2015-09-17 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.
Illumina Clinical Services Laboratory,Illumina RCV000406425 SCV000356295 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000300038 SCV000356296 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589910 SCV000697623 benign not provided 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.4734C>T (p.Pro1578Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 80/89090 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.001592 (79/49632). This frequency is about 29 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, due to the synonymous nature of this variant, the lack of predicted effect on splicing, and the relatively high frequency in the control population, this variant is classified as benign.
Invitae RCV000406425 SCV000554609 benign Catecholaminergic polymorphic ventricular tachycardia 2017-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036755 SCV000060410 likely benign not specified 2012-05-17 criteria provided, single submitter clinical testing Pro1578Pro in exon 36 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 4/6620 European Ame rican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Pro1578Pro in exon 36 of RYR2 (allele fr equency = 4/6620) **

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