ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.4966G>T (p.Glu1656Ter) (rs62638179)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000086294 SCV000890285 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing The E1656X nonsense variant in the CEP290 gene has been reported previously in multiple unrelated individuals with Leber congenital amaurosis who also had a second CEP290 variant identified (den Hollander et al, 2006; Collison et al., 2015; Sheck et al., 2018). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E1656X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, E1656X is considered to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000263885 SCV000381416 likely pathogenic CEP290-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The CEP290 c.4966G>T (p.Glu1656Ter) variant is a stop-gained variant predicted to result in a premature truncation of the protein. The p.Glu1656Ter variant has been reported in three studies in patients with CEP290-related disorders in which it is found in a total of four affected individuals with Leber congenital amaurosis including three in a compound heterozygous state, all with the same known pathogenic stop-gained variant on the second allele, and one in a heterozygous state (den Hollander et al. 2006; Walia et al. 2010; Halbritter et al. 2013). This variant has not been reported in the literature in individuals with other CEP290-related phenotypes. The p.Glu1656Ter variant was absent from 192 controls and is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium though this is based on only two alleles in a region of good sequence coverage so the variant is presumed rare. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Glu1656Ter 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 RCV000637002 SCV000758450 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1656*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62638179, ExAC 0.02%). This variant has been reported as single heterozygous or biallelic with other pathogenic CEP290 variants in individuals with Leber congenital amaurosis (PMID: 16909394, 20079931, 23559409), Joubert syndrome (PMID: 28497568) or nephronophthisis-associated ciliopathy (PMID: 23188109). ClinVar contains an entry for this variant (Variation ID: 99857). 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.
Retina International RCV000086294 SCV000118440 not provided not provided no assertion provided not provided

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