ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25525159, 21937013, 27356891, 19802896, 15852235, 29357828, 18234728, 17028174, 37417625)

The FLCN c.1432+1G>A variant (rs755959303), also known as IVS12+1G>A, is reported in the literature in an individual with Birt-Hogg-Dube syndrome (Toro 2008) and an individual with colorectal cancer (Dobbins 2016). This variant is classified as likely pathogenic or pathogenic in ClinVar (Variation ID: 253252). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 12, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. REFERENCES Dobbins SE et al. Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. Fam Cancer. 2016 Oct;15(4):593-9. Toro JR et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31.

This sequence change affects a donor splice site in intron 12 of the FLCN 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 FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with biopsy confirmed fibrofolliculoma(s) and/or Birt-Hogg-Dubé syndrome (PMID: 18234728, 27356891; Invitae). ClinVar contains an entry for this variant (Variation ID: 253252). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The c.1432+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the FLCN gene. This mutation (designated IVS12+1G>A) has been identified in an individual with a personal medical history of lung cysts, pneumothorax, and skin findings characteristic of Birt-Hogg-Dube syndrome (Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

PP4, PM2, PVS1_moderate