Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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. |
Invitae | 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, |
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, |
RCV001829491 | SCV002094935 | uncertain significance | Leber congenital amaurosis | 2020-03-03 | no assertion criteria provided | clinical testing |