ClinVar Genomic variation as it relates to human health

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000217639). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: CEP290 c.4522C>T (p.Arg1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4522C>T has been reported in the literature in individuals affected with CEP290-related disorders, including Leber congenital amaurosis and Joubert syndrome (e.g. Rachel_2012, Bachmann-Gagescu_2015, Diderich_2021, Ginevrino_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence and demonstrated ciliation defects in fibroblasts from a patient, who carried another pathogenic variant in trans (Vandervore_2019). Eight ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217639). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs749439750, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg1508*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115).

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35314707, 26092869)