Submissions for variant NM_025114.4(CEP290):c.4437+1G>A

gnomAD frequency: 0.00009  dbSNP: rs760915898

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000498064	SCV000339179	pathogenic	not provided	2016-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473837	SCV000541577	likely pathogenic	Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 34 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 (rs760915898, gnomAD 0.01%). 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: 285948). 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.
GeneDx	RCV000498064	SCV000589312	likely pathogenic	not provided	2025-03-03	criteria provided, single submitter	clinical testing	Reported in a patient with developmental delay, infantile spasms, renal cysts and nephronophthisis; however, this patient also had a variant in a candidate gene that may be related to the phenotype (PMID: 30311385); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30267408, 31964843, 30311385)
Fulgent Genetics, Fulgent Genetics	RCV000763313	SCV000893990	likely pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2018-10-31	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000779117	SCV001251488	likely pathogenic	CEP290-related disorder		criteria provided, single submitter	research	The CEP290 c.4437+1G>A (p.?) variant is predicted to disrupt a canonical splice donor site, which may result in an aberrant protein. This variant has not been reported in association with CEP290-related disorders.
Revvity Omics, Revvity	RCV000498064	SCV002017029	pathogenic	not provided	2019-09-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000498064	SCV002067301	likely pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CEP290 gene demonstrated a sequence change in the canonical splice donor site of intron 34, c.4437+1G>A. This sequence change is predicted to disrupt the canonical splice donor site, and affect normal splicing of exon 34. This c.4437+1G>A change does not appear to have been previously described in individuals with CEP290-related disorders. This sequence change has been described in the gnomAD database in the non-Finnish European subpopulation with a low frequency of 0.013% (dbSNP rs760915898). Collectively, this evidence suggests c.4437+1G>A is likely pathogenic, however, functional studies have not been performed to prove this conclusively.
Natera, Inc.	RCV001271571	SCV001452836	likely pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000779117	SCV004105717	likely pathogenic	CEP290-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The CEP290 c.4437+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been observed in a large dataset of worldwide populations used to evaluate the frequency or percentage of individuals carrying a disease-causing variant in genes associated with autosomal recessive inherited retinal diseases (IRDs) (Table S3, Hanany et al. 2020. PubMed ID: 31964843). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CEP290 are expected to be pathogenic. This variant is interpreted as likely pathogenic.