Submissions for variant NM_025114.4(CEP290):c.4C>T (p.Pro2Ser)

gnomAD frequency: 0.00001  dbSNP: rs1064795491

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478865	SCV000571349	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The P2S variant in the CEP290 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P2S variant was not observed 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 P2S 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 P2S as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001373838	SCV001570570	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 2 of the CEP290 protein (p.Pro2Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). 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: 421994). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Natera, Inc.	RCV001835818	SCV002094950	uncertain significance	Leber congenital amaurosis	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732900	SCV005354939	uncertain significance	CEP290-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The CEP290 c.4C>T variant is predicted to result in the amino acid substitution p.Pro2Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.