ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.6645+1G>A (rs201218801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454208 SCV000538016 likely pathogenic Joubert syndrome 5 2016-03-30 criteria provided, single submitter clinical testing This c.6645+1G>A variant is predicted to affect the splice-donor site in intron 48 of the CEP290 gene. The frequency of this variant is very low in the ExAC database and is absent in both the 1000 Genomes and Exome Sequencing Project databases. In addition, splice-site computational algorithms have predicted this variant to abrogate splicing. Loss-of-function mutations are a known mechanism of disease for this disorder; therefore, we have provisionally classified this variant as Likely Pathogenic. We have confirmed this sequence change in our laboratory using Sanger sequencing. However, splicing studies are necessary to confirm this interpretation.
GeneDx RCV000497486 SCV000590762 uncertain significance not provided 2018-03-26 criteria provided, single submitter clinical testing The c.6645+1G>A pathogenic variant in the CEP290 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 48. 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. The c.6645+1G>A variant is observed in 2/4584 (0.04%) alleles from individuals of Latino background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.6645+1G>A as a variant of uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000497486 SCV000701396 likely pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing
Invitae RCV000801486 SCV000941263 likely pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2020-10-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 48 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 (rs201218801, ExAC 0.04%). This variant has not been reported in the literature in individuals with CEP290-related disease. ClinVar contains an entry for this variant (Variation ID: 290046). 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.
Baylor Genetics RCV001331377 SCV001523408 likely pathogenic Meckel syndrome, type 4 2019-09-06 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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