ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.4063C>T (p.Arg1355Cys)

gnomAD frequency: 0.00006  dbSNP: rs376425111
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000994955 SCV001148791 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001236001 SCV001408712 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2022-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1355 of the CEP290 protein (p.Arg1355Cys). 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 missense change has been observed in individual(s) with early childhood onset retinal dystrophy (PMID: 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 806918). 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 expected to disrupt CEP290 protein function. 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 RCV002481769 SCV002776951 uncertain significance Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2022-03-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV001279536 SCV001466633 uncertain significance Leber congenital amaurosis 2020-08-04 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004544996 SCV004768687 uncertain significance CEP290-related disorder 2024-07-29 no assertion criteria provided clinical testing The CEP290 c.4063C>T variant is predicted to result in the amino acid substitution p.Arg1355Cys. This variant was reported in the compound heterozygous state in an individual with early childhood onset retinal dystrophy (Patient 431 in Supplementary Table 1, Stone et al 2017. PubMed ID: 28559085). This variant is reported in 0.0084% 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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