ClinVar Genomic variation as it relates to human health

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30902645)

Variant summary: CEP290 c.4813-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7e-05 in 86284 control chromosomes (gnomAD). c.4813-2A>G has been reported in the literature as a homozygous genotype in at-least one Spanish individual affected with an Inherited Retinal Disease (IRD) phenotype who also harbored another reportedly pathogenic homozygous variant in the NR2E3 gene (c.731del) presenting with clinical features characteristic of two different phenotypic entities (Martin-Merida_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change affects an acceptor splice site in intron 36 of the CEP290 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs369523378, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with CEP290-related conditions (PMID: 30902645). ClinVar contains an entry for this variant (Variation ID: 432415). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The CEP290 c.4813-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. While this variant disrupts the canonical splice acceptor site, it is also predicted to activate a cryptic splice acceptor site 15 nucleotides into the exon (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). The activation of the cryptic splice site is predicted to delete 5 amino acids. This variant has been reported in the homozygous state in an individual with retinitis pigmentosa; however, this individual also harbored a homozygous NR2E3 frameshift variant (Family RP-2350 in Figure S4, Martin-Merida et al. 2019. PubMed ID: 30902645). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD, indicating it is relatively common in this population. This variant is interpreted as likely pathogenic.