ClinVar

Description

Variant summary: TULP1 c.1496-6C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predict a significant impact on normal splicing by abolishing a 3 prime acceptor site, while three predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 248766 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis (8.8e-05 vs 0.0005), allowing no conclusion about variant significance. c.1496-6C>A has been reported in the literature in multiple individuals affected with Retinitis pigmentosa or retinal degeneration. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.