ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.451C>T (p.Arg151Ter) (rs757641323)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000414162 SCV000885166 likely pathogenic not provided 2017-07-30 criteria provided, single submitter clinical testing The CEP290 c.451C>T;p.Arg151Ter variant has been described in at least one individual with retinal dystrophy (Huang 2015) and one family with early onset severe retinal dystrophy and Leber congential amaurosis (Littink 2010). The variant is listed in the ClinVar database (Variation ID: 372761) and the dbSNP variant database (rs757641323) but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, but at least one report shows that this variant leads to a skipping of exon 7 or exon 7 and 8, which leads to an in-frame product lacking a portion of a functional domain. Considering available information, this variant is classified as likely pathogenic. References: Huang XF et al. Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet Med. 2015 Apr;17(4):271-8. Littink KW et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3646-52.
GeneDx RCV000414162 SCV000491224 pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing The R151X variant in the CEP290 gene has been reported previously in association with Leber congenital amaurosis, early-onset severe retinal dystrophy, and a nonspecified retinal dystrophy (Littink et al., 2010; Huang et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R151X variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, we interpret R151X as a pathogenic variant.
Invitae RCV000552078 SCV000634657 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2017-02-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 151 (p.Arg151*) of the CEP290 gene. This variant has been reported in an individual with inherited retinal dystrophy (PMID: 25356976), and has been shown to to segregate with early-onset severe retinal dystrophy in a single family (PMID: 20130272). An experimental study has shown that cells from individuals heterozygous for this variant and a second variant in CEP290 express mRNA isoforms lacking exon 7 or exons 7-8, which result in shortened transcripts that would bypass this nonsense variant (PMID: 20130272). This may result in production of a shortened protein product, although the clinical significance of this shortened protein is unknown. In summary, this is a rare nonsense variant that is expected to result in either an absent protein due to nonsense mediated decay or an in-frame deletion due to a change in RNA splicing. While the definite impact of this variant on protein function is unknown, it has been shown to segregate with disease in several affected individuals. Therefore, this variant has been classified as Pathogenic.

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