Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_025114.4(CEP290):c.4438-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,519,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-88084854-TG-T is Pathogenic according to our data. Variant chr12-88084854-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449448.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=4}. Variant chr12-88084854-TG-T is described in Lovd as [Likely_pathogenic].
Uncertain significance, criteria provided, single submitter
research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Dec 03, 2018
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). -
Likely pathogenic, criteria provided, single submitter
research
Ocular Genomics Institute, Massachusetts Eye and Ear
Apr 08, 2021
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. -
CEP290-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Dec 28, 2023
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. -
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, no assertion criteria provided
clinical testing
Natera, Inc.
Oct 18, 2021
- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Apr 26, 2021
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) -
Bardet-Biedl syndrome 14 Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Feb 22, 2024
- -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Oct 08, 2023
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. -
Retinopathy Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana