ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs201218801
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Total submissions: 11
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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 2022-04-19 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29754767)
Eurofins Ntd Llc (ga) RCV000497486 SCV000701396 likely pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing
Invitae RCV000801486 SCV000941263 likely pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2023-12-19 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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs201218801, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. 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. 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].
CeGaT Center for Human Genetics Tuebingen RCV000497486 SCV001961366 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing
Suma Genomics RCV001833396 SCV002097003 pathogenic Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 criteria provided, single submitter clinical testing
New York Genome Center RCV002467720 SCV002764443 likely pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5 2020-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002522012 SCV003695995 uncertain significance Inborn genetic diseases 2021-09-21 criteria provided, single submitter clinical testing Punj, 2018_x000D_ _x000D_ Resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004537606 SCV004116654 likely pathogenic CEP290-related disorder 2023-11-20 criteria provided, single submitter clinical testing The CEP290 c.6645+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in association with CEP290-related disease. This variant is reported in 0.019% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-88453674-C-T). Splicing variants in CEP290 have been reported in patients with Joubert Syndrome, Meckel Syndrome, and Leber Congenital Amaurosis and are expected to be pathogenic (Baala et al. 2007. PubMed ID: 17564974; Perrault et al. 2007. PubMed ID: 17345604; Tory et al. 2007. PubMed ID: 17409309). This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003463776 SCV004214821 likely pathogenic Bardet-Biedl syndrome 14 2023-10-31 criteria provided, single submitter clinical testing

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