ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.1429C>T (p.Arg477Ter) (rs1170451277)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763316 SCV000893993 pathogenic Leber congenital amaurosis 10; Meckel syndrome type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000627200 SCV000748185 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing The R477X nonsense variant in the CEP290 gene has been reported previously in an individual with Leber congenital amaurosis who had a second CEP290 variant identified (Wiszniewski et al., 2011). The R477X variant was also observed in apparent homozygous state in a patient with Meckel-Gruber syndrome (Szymanska et al., 2012). The R477X variant is not observed in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Illumina Clinical Services Laboratory,Illumina RCV000779118 SCV000915612 likely pathogenic CEP290-Related Disorders 2018-12-04 criteria provided, single submitter clinical testing The CEP290 c.1429C>T (p.Arg477Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg477Ter variant has been reported in at least three studies in which it is found in three individuals including one individual with Meckel syndrome in whom the variant was present in a homozygous state and two individuals with Leber congenital amaurosis in whom the variant was present in a compound heterozygous state with a splice variant on the second allele (Wiszniewski et al. 2011; Szymanska et al. 2012; Wang et al. 2015). The p.Arg477Ter variant was absent from 192 controls (Wiszniewski et al. 2011; Szymanska et al. 2012), and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Arg477Ter variant is classified as likely pathogenic for CEP290-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000814304 SCV000954707 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-08-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg477*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with CEP290-related conditions (PMID: 21153841, 23351400). ClinVar contains an entry for this variant (Variation ID: 523768). Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). For these reasons, this variant has been classified as Pathogenic.

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