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

gnomAD frequency: 0.00001  dbSNP: rs587783009

Total submissions: 6

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	2024-03-17	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