Submissions for variant NM_025114.4(CEP290):c.4813-2A>G

gnomAD frequency: 0.00046  dbSNP: rs369523378

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498458	SCV000590137	pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30902645)
Eurofins Ntd Llc (ga)	RCV000498458	SCV000704390	likely pathogenic	not provided	2016-12-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687629	SCV000815208	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 36 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 (rs369523378, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with CEP290-related conditions (PMID: 30902645). ClinVar contains an entry for this variant (Variation ID: 432415). 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.
Blueprint Genetics	RCV001075395	SCV001241017	likely pathogenic	Retinal dystrophy	2018-07-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535842	SCV001752450	likely pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-03-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000498458	SCV002025156	likely pathogenic	not provided	2023-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222534	SCV002500607	likely pathogenic	CEP290-related disorder	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.4813-2A>G 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: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7e-05 in 86284 control chromosomes (gnomAD). c.4813-2A>G has been reported in the literature as a homozygous genotype in at-least one Spanish individual affected with an Inherited Retinal Disease (IRD) phenotype who also harbored another reportedly pathogenic homozygous variant in the NR2E3 gene (c.731del) presenting with clinical features characteristic of two different phenotypic entities (Martin-Merida_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 likely pathogenic.
Mendelics	RCV002248731	SCV002518662	pathogenic	Joubert syndrome 5	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003464071	SCV004214831	likely pathogenic	Bardet-Biedl syndrome 14	2024-03-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271569	SCV001452834	likely pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002222534	SCV004118526	likely pathogenic	CEP290-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The CEP290 c.4813-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. While this variant disrupts the canonical splice acceptor site, it is also predicted to activate a cryptic splice acceptor site 15 nucleotides into the exon (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). The activation of the cryptic splice site is predicted to delete 5 amino acids. This variant has been reported in the homozygous state in an individual with retinitis pigmentosa; however, this individual also harbored a homozygous NR2E3 frameshift variant (Family RP-2350 in Figure S4, Martin-Merida et al. 2019. PubMed ID: 30902645). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD, indicating it is relatively common in this population. This variant is interpreted as likely pathogenic.