ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.1781T>A (p.Leu594Ter)

gnomAD frequency: 0.00001  dbSNP: rs371496675
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522611 SCV000618465 pathogenic not provided 2019-06-26 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27208204, 29398085, 29178642, 31980526)
Labcorp Genetics (formerly Invitae), Labcorp RCV001389936 SCV001591485 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2024-09-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu594*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs371496675, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 27208204, 29178642). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 236468). 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.
Fulgent Genetics, Fulgent Genetics RCV002500754 SCV002810559 pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2024-04-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV003463626 SCV004214852 pathogenic Bardet-Biedl syndrome 14 2024-01-22 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals RCV000225634 SCV000282574 likely pathogenic Retinal dystrophy no assertion criteria provided clinical testing
Natera, Inc. RCV001274126 SCV001457922 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004532829 SCV004728048 likely pathogenic CEP290-related disorder 2024-02-08 no assertion criteria provided clinical testing The CEP290 c.1781T>A variant is predicted to result in premature protein termination (p.Leu594*). This variant was reported in the compound heterozygous state in at least one individual with Leber congenital amaurosis (Table S5, Ellingford et al 2016. PubMed ID: 27208204; Thompson et al. 2017. PubMed ID: 29178642; Sheck et al. 2018. PubMed ID: 29398085). This variant is reported in 0.0041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CEP290 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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