ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.3175dupA (p.Ile1059Asnfs) (rs62640570)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000114193 SCV000147746 pathogenic Meckel-Gruber syndrome 2013-08-02 criteria provided, single submitter clinical testing
UW Hindbrain Malformation Research Program,University of Washington RCV000201666 SCV000256384 pathogenic Joubert syndrome 5 2015-02-23 criteria provided, single submitter research
GeneDx RCV000086287 SCV000589618 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing The c.3175dupA variant in the CEP290 gene has been reported multiple times previously in association with CEP290-related disorders (Sayer et al., 2006; Chaki et al., 2011; Yzer et al., 2012). The c.3175dupA variant causes a frameshift starting with codon Isoleucine 1059, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ile1059AsnfsX11. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3175dupA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.3175dupA as a pathogenic variant.
Invitae RCV000695282 SCV000823771 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2018-05-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile1059Asnfs*11) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in combination with other CEP290 variants in individuals affected with Leber congenital amaurosis and/or Joubert syndrome, including at least one individual where the variant was reported on the opposite chromosome (in trans) from a likely pathogenic variant (PMID: 16682973, 17345604, 22355252, 21245082, 25920555). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.3175-3176insA and c.3175insA in the literature. ClinVar contains an entry for this variant (Variation ID: 99850). 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 RCV000086287 SCV000118433 not provided not provided no assertion provided not provided

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