ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.3593C>T (p.Ser1198Leu)

gnomAD frequency: 0.00003  dbSNP: rs372640024
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000488171 SCV000571049 uncertain significance not provided 2016-07-26 criteria provided, single submitter clinical testing The S1198L variant in the CEP290 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S1198L variant was not observed at any significant frequency in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1198L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S1198L as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV000488171 SCV000574938 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Invitae RCV001248616 SCV001422115 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1198 of the CEP290 protein (p.Ser1198Leu). This variant is present in population databases (rs372640024, gnomAD 0.02%). 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: 421751). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Baylor Genetics RCV001331375 SCV001523405 uncertain significance Senior-Loken syndrome 6 2019-09-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics RCV002489164 SCV002793149 uncertain significance Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2022-04-07 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000488171 SCV003831583 uncertain significance not provided 2019-07-11 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003419809 SCV004113444 uncertain significance CEP290-related condition 2023-01-20 criteria provided, single submitter clinical testing The CEP290 c.3593C>T variant is predicted to result in the amino acid substitution p.Ser1198Leu. This has been previously observed and reported as a variant of uncertain significance in a cohort of individuals with syndromic/non-syndromic inherited retinal dystrophies and/or optic nerve disorders (Table S12, Diñeiro. 2020. PubMed ID: 32483926). This variant is reported in 0.021% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-88483245-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001828502 SCV002094257 uncertain significance Leber congenital amaurosis 2020-02-26 no assertion criteria provided clinical testing

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