ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.4438-3del (rs747323414)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521335 SCV000617618 likely pathogenic not provided 2017-03-08 criteria provided, single submitter clinical testing The c.4438-3delC variant in the CEP290 gene has been reported previously with Leber congenital amaurosis in theheterozygous state and in individuals who also harbored a second CEP290 variant, although parental studies were notperformed to determine the phase of these two variants (Pasadhika et al., 2010; Wiszniewski et al., 2011; Collison etal., 2015). This variant reduces the quality of the splice acceptor site in intron 34, and is expected to cause abnormalgene splicing. The c.4438-3delC variant is not observed at a significant frequency in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.4438-3delC as a likelypathogenic variant.
Invitae RCV000541615 SCV000634656 likely pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-12-14 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs747323414, ExAC 0.02%). This variant has been observed in individuals affected with Leber congenital amaurosis (PMID: 19959640, 21153841, 26529047, Invitae database). ClinVar contains an entry for this variant (Variation ID: 449448). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626965 SCV000747668 uncertain significance Retinopathy 2017-01-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute 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,; 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).

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