ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.5012+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1369768287
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000595159 SCV000702464 likely pathogenic not provided 2016-10-03 criteria provided, single submitter clinical testing
Invitae RCV001056739 SCV001221201 likely pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2023-03-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 37 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). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 497762). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%).
Fulgent Genetics, Fulgent Genetics RCV002491180 SCV002802182 likely pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2021-10-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003465334 SCV004216609 likely pathogenic Bardet-Biedl syndrome 14 2023-06-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003485612 SCV004240874 likely pathogenic Meckel syndrome, type 4 2023-12-11 criteria provided, single submitter clinical testing Variant summary: CEP290 c.5012+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 135692 control chromosomes. To our knowledge, no occurrence of c.5012+2T>C in individuals affected with Meckel Syndrome Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001276491 SCV001462870 likely pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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