ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.6818_6818+1dup (rs1060499781)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000813873 SCV000954254 likely pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-11-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 49 of the CEP290 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CEP290-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000454358 SCV000538015 likely pathogenic Joubert syndrome 5 2016-03-30 criteria provided, single submitter clinical testing The c.6818+1_6818+2insGG splice variant in the CEP290 gene has not been previously reported in published literature and is absent from the population databases (ESP; 1000 Genomes; ExAC). Splice-site, nonsense, and frameshift variants have been described in the CEP290 gene in several affected individuals (including nonsense and frameshift variants downstream of this splice variant) and thus, loss of function is a known mechanism of disease. In silico splicing algorithms predict this variant will cause altered splicing (Human Splice Finder = Broken WT Donor Site, New Donor Site). Therefore, this collective evidence supports the classification of the c.6818+1_6818+2insGG as a Likely Pathogenic variant for Joubert Syndrome and Related Disorders. Because this gene is expressed in blood cells, RNA-splicing studies can be performed to validate this classification (see recommendation).

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