ClinVar Genomic variation as it relates to human health

Variant summary: FCSK c.1407-1G>C 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' acceptor site and also creates a new 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. Additionally, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in this gene are causitive of disease. The variant was absent in 259244 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1407-1G>C in individuals affected with Congenital Disorder Of Glycosylation With Defective Fucosylation and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.019%). This variant on the canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. A pathogenic loss-of-function variant is reported downstream of the variant. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

This variant has not been reported in the literature in individuals affected with FUK-related conditions. This variant is present in population databases (rs201291016, gnomAD 0.04%). This sequence change affects an acceptor splice site in intron 14 of the FUK 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in FUK cause disease. ClinVar contains an entry for this variant (Variation ID: 1705108). 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 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.