Submissions for variant NM_025114.4(CEP290):c.4438-3del

gnomAD frequency: 0.00004  dbSNP: rs747323414

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521335	SCV000617618	likely pathogenic	not provided	2021-04-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19959640, 21153841, 26529047)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541615	SCV000634656	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 34 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs747323414, gnomAD 0.01%). This variant has been observed in individuals with Leber congenital amaurosis (PMID: 19959640, 21153841, 26529047; Invitae). ClinVar contains an entry for this variant (Variation ID: 449448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626965	SCV000747668	uncertain significance	Retinal disorder	2017-01-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004997	SCV001164555	uncertain significance	Leber congenital amaurosis 10	2018-12-03	criteria provided, single submitter	research	The heterozygous c.4438-3delC variant in CEP290 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Leber congenital amaurosis. The presence of this variant in combination with a likely pathogenic variant increases the likelihood that the c.4438-3delC variant is pathogenic. The c.4438-3delC variant in CEP290 has not been previously reported in individuals with Leber congenital amaurosis but has been identified in 0.002716% (5/184078) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747323414). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 3' splice region. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, additional studies are required to fully establish its clinical significance and the c.4438-3delC variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting (Richards 2015).
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001004997	SCV001573635	likely pathogenic	Leber congenital amaurosis 10	2021-04-08	criteria provided, single submitter	research	The CEP290 c.4438-3del 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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.
Baylor Genetics	RCV003464110	SCV004214850	likely pathogenic	Bardet-Biedl syndrome 14	2024-02-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787831	SCV005400528	pathogenic	CEP290-related ciliopathy	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 5 (MIM#610188), Leber congenital amaurosis 10 (MIM#611755), Meckel syndrome 4 (MIM#611134) and Senior-Loken syndrome 6 (MIM#610189). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (35 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported four times as likely pathogenic, once as pathogenic and once as a VUS (ClinVar) and in seven compound heterozygous individuals with Leber congenital amaurosis or undefined retinal disease (PMID: 37510321, 26529047, 33749171, 28559085, 21153841). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_025114.4(CEP290):c.1219_1220del (p.Met407Glufs*14)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005010477	SCV005630050	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2024-01-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829483	SCV002094222	likely pathogenic	Leber congenital amaurosis	2021-10-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537872	SCV004120457	likely pathogenic	CEP290-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The CEP290 c.4438-3delC variant is predicted to result in an intronic deletion. This variant is predicted to significantly weaken the acceptor splice site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751) and has been reported along with a second causative variant in multiple unrelated patients with Leber congenital amaurosis (LCA) (Pasadhika et al. 2010. PubMed ID: 19959640, reported as IVS34-3 del1gC; Wiszniewski et al. 2011. PubMed ID: 21153841; Collison et al. 2015. PubMed ID: 26529047). This variant is reported in 0.010% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.