ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.7328_7332dup (p.Val2445fs)

dbSNP: rs747138345
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000821112 SCV000961855 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2024-01-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val2445Argfs*3) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the CEP290 protein. This variant is present in population databases (rs775531853, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 663263). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Leu2448Thrfs*8) have been determined to be pathogenic (PMID: 16682973, 16909394, 29588463). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002487837 SCV002778616 pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2024-03-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV003461271 SCV004214853 pathogenic Bardet-Biedl syndrome 14 2023-10-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV004029060 SCV004926252 pathogenic Inborn genetic diseases 2024-02-20 criteria provided, single submitter clinical testing The c.7328_7332dupAGAAG (p.V2445Rfs*3) alteration, located in exon 54 (coding exon 53) of the CEP290 gene, consists of a duplication of AGAAG at position 7328, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration occurs at the 3' terminus of the CEP290 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 1.4% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the AGAAGAGAAG allele has an overall frequency of 0.004% (9/246068) total alleles studied. The highest observed frequency was 0.05% (9/17952) of East Asian alleles. This variant has been identified likely in trans with another CEP290 variant in multiple individuals with features consistent with CEP290-related ciliopathy (Liu, 2021; Xu, 2020; Xu, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Natera, Inc. RCV001830808 SCV002091809 pathogenic Leber congenital amaurosis 2021-07-10 no assertion criteria provided clinical testing

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