ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.4813-2A>G (rs369523378)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498458 SCV000704390 likely pathogenic not provided 2016-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000498458 SCV000590137 likely pathogenic not provided 2017-06-06 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the CEP290 gene. The c.4813-2 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.4813-2 A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.4813-2 A>G splice site variant destroys the canonical splice acceptor site in intron 36. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000687629 SCV000815208 likely pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-01-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 36 of the CEP290 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs369523378, ExAC 0.08%). This variant has not been reported in the literature in individuals with CEP290-related disease. ClinVar contains an entry for this variant (Variation ID: 432415). 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.

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