ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.1711+1G>A

gnomAD frequency: 0.00001  dbSNP: rs587783009
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001384909 SCV001584586 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2022-11-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as 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: 156377). Disruption of this splice site has been observed in individuals with Leber congenital amaurosis and Joubert syndrome (PMID: 25445212, 32139166). This variant is present in population databases (rs587783009, gnomAD 0.009%). This sequence change affects a donor splice site in intron 17 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).
Fulgent Genetics, Fulgent Genetics RCV002492522 SCV002800668 likely pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2021-08-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387770 SCV004100181 pathogenic CEP290-related disorder 2023-09-26 criteria provided, single submitter clinical testing Variant summary: CEP290 c.1711+1G>A 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: Three predict the variant abolishes a 5' splicing donor site. At least one publication confirmed that this variant affects mRNA splicing by analyzing patient derived fibroblast cDNA (Itoh_2018). The variant allele was found at a frequency of 1.2e-05 in 164036 control chromosomes (gnomAD). c.1711+1G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with CEP290-related disorders, including Leber congenital amaurosis and Joubert syndrome (e.g. Itoh_2018, Seong_2015, Devi_2020, Kim_2021). Morphological analysis of cultured fibroblasts from a compound heterozygous patient revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium (Itoh_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29217415, 25445212, 32139166, 33946315). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003467201 SCV004216555 pathogenic Bardet-Biedl syndrome 14 2023-08-22 criteria provided, single submitter clinical testing
Dept Of Ophthalmology, Nagoya University RCV003888575 SCV004707703 pathogenic Retinal dystrophy 2023-10-01 criteria provided, single submitter research
Molecular Diagnostics Laboratory, Seoul National University Hospital RCV000144459 SCV000189593 pathogenic Leber congenital amaurosis 10 2014-09-18 no assertion criteria provided clinical testing

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