ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.1387G>A (p.Val463Ile)

gnomAD frequency: 0.00003  dbSNP: rs558414868
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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 RCV000555543 SCV000634637 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 463 of the CEP290 protein (p.Val463Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 461775). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP290 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002483396 SCV002784362 uncertain significance Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2022-05-12 criteria provided, single submitter clinical testing
GeneDx RCV004760563 SCV005369791 uncertain significance not provided 2023-05-31 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001835848 SCV002094332 uncertain significance Leber congenital amaurosis 2019-10-28 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004537947 SCV004723552 uncertain significance CEP290-related disorder 2024-06-03 no assertion criteria provided clinical testing The CEP290 c.1387G>A variant is predicted to result in the amino acid substitution p.Val463Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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