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

gnomAD frequency: 0.00003  dbSNP: rs372640024

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	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	RCV000488171	SCV003831583	uncertain significance	not provided	2019-07-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535521	SCV004113444	uncertain significance	CEP290-related disorder	2023-12-19	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 et al. 2020. PubMed ID: 32483926). This variant is reported in 0.021% of alleles in individuals of Latino descent in gnomAD. 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