Submissions for variant NM_025114.4(CEP290):c.502C>T (p.Arg168Cys)

dbSNP: rs760856790

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519720	SCV000618850	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CEP290 gene. The R168C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R168C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is not conserved. However, the R168C 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036439	SCV001199804	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2021-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 168 of the CEP290 protein (p.Arg168Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 28771248). ClinVar contains an entry for this variant (Variation ID: 450290). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778989	SCV002015112	uncertain significance	not specified	2021-10-28	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.502C>T (p.Arg168Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 214098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.502C>T has been reported in the literature in an individual affected with Joubert syndrome and an individual affected with Pituitary stalk interruption syndrome (Phelps_2018, Fang_2020). These reports do not provide unequivocal conclusions about association of the variant with CEP290-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001829491	SCV002094935	uncertain significance	Leber congenital amaurosis	2020-03-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732928	SCV005348869	uncertain significance	CEP290-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The CEP290 c.502C>T variant is predicted to result in the amino acid substitution p.Arg168Cys. This variant has been reported in an individual with Joubert syndrome (Supplementary Appendix 3, Phelps et al. 2018. PubMed ID: 28771248). This variant has also been reported in an individual undergoing testing for pituitary stalk interruption syndrome (Fang et al. 2020. PubMed ID: 32864857). This variant is reported in 0.0058% of alleles in individuals of East Asian descent in gnomAD. A different missense change impacting the same amino acid (c.503G>A, p.Arg168His) has been reported in an individual with retinitis pigmentosa (Table S4, Jespersgaard et al. 2019. PubMed ID: 30718709). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.