Submissions for variant NM_025114.4(CEP290):c.2991+1655A>G

gnomAD frequency: 0.00029  dbSNP: rs281865192

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086286	SCV000329242	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Reported as the most common pathogenic variant among individuals of North American and North Western European background (PMID: 16909394, 34196655); Published functional studies demonstrate a damaging effect resulting in the insertion of an aberrant exon into approximately half of CEP290 transcripts and reduced CEP290 mRNA levels in comparison to wild type (PMID: 25761237, 23344081); This variant is associated with the following publications: (PMID: 22842229, 20683928, 20805370, 27106101, 31429209, 23591405, 19823873, 24767827, 17564967, 17345604, 20130272, 23344081, 23343883, 18682808, 20690115, 22355252, 28224992, 24223178, 29186038, 29178642, 30576320, 31087526, 30559420, 31734136, 34327195, 32531858, 32865313, 29398085, 29518907, 33726816, 32037395, 31816670, 28619647, 28510626, 16909394, 25761237, 34196655, 30193310)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558460	SCV000634646	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs281865192, gnomAD 0.02%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 16909394, 17345604, 17964524). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS26+1655A>G and p.Cys998X. ClinVar contains an entry for this variant (Variation ID: 1337). Studies have shown that this variant results in insertion of 128bp of intronic sequence between exons 26 and 27 and introduces a premature termination codon (PMID: 16909394, 23344081). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000086286	SCV000700700	pathogenic	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763315	SCV000893992	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-02-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000988884	SCV001138782	pathogenic	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075828	SCV001241465	pathogenic	Retinal dystrophy	2019-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086286	SCV001246570	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196010	SCV001366439	pathogenic	Joubert syndrome 5	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM3,PP3,PP4.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001255341	SCV001431671	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000086286	SCV001447854	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000001400	SCV001548124	likely pathogenic	Leber congenital amaurosis 10	2021-01-30	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000001400	SCV001573634	pathogenic	Leber congenital amaurosis 10	2021-04-08	criteria provided, single submitter	research	The CEP290 c.2991+1655A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731267	SCV001983668	pathogenic	CEP290-related disorder	2021-09-16	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.2991+1655A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic intronic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and leads to insertion of a cryptic exon encoding a premature stop codon (den Hollander_2006). The variant allele was found at a frequency of 0.00013 in 31310 control chromosomes. c.2991+1655A>G has been reported in the literature in multiple individuals affected with CEP290-Related Disorders, namely Leber Congenital Amaurosis (example, den Hollander_2006). These data indicate that the variant is very likely to be associated with disease. Functional studies have reported ciliary and axonemal defects in patients with this variant (Gerard_2012). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000086286	SCV002017032	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460403	SCV004214830	pathogenic	Bardet-Biedl syndrome 14	2024-03-27	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV001196010	SCV004847136	pathogenic	Joubert syndrome 5	2023-10-16	criteria provided, single submitter	clinical testing
OMIM	RCV000001400	SCV000021550	pathogenic	Leber congenital amaurosis 10	2007-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000001400	SCV000058614	pathologic	Leber congenital amaurosis 10	2012-03-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
GeneReviews	RCV000001400	SCV000087012	not provided	Leber congenital amaurosis 10		no assertion provided	literature only
Retina International	RCV000086286	SCV000118432	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678535	SCV000804609	pathogenic	Retinitis pigmentosa	2016-09-01	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000086286	SCV001922270	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000086286	SCV001932539	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086286	SCV002037574	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831503	SCV002094277	pathogenic	Leber congenital amaurosis	2017-09-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001731267	SCV004116303	pathogenic	CEP290-related disorder	2024-05-26	no assertion criteria provided	clinical testing	The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This deep intronic variant (also referred to as IVS26+1655A>G) has been reported to create a strong splice-donor site and insert a cryptic exon in the CEP290 transcript (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been reported, in the homozygous or compound heterozygous state along with a second CEP290 variant, in 16 of 76 unrelated patients with autosomal recessive Leber congenital amaurosis (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/1337/). Given the evidence, we interpret c.2991+1655A>G as pathogenic.