ClinVar

Description

The c.1062+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the FLCN gene. This mutation has been detected in numerous individuals meeting clinical diagnostic criteria for Birt-Hogg-Dube syndrome (BHD) (Schmidt LS et al. Am J Hum Genet. 2005 Jun;76(6):1023-33; Gad S et al. Br J Cancer. 2007 Jan 29;96(2):336-40; Toro JR et al. J Med Genet. 2008 Jun;45(6):321-31; Benusiglio PR et al. Orphanet J Rare Dis. 2014 Oct 29;9:163; Whitworth J et al. JAMA Oncol. 2016 Mar;2(3):373-9; Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). While this mutation has been identified in BHD patients of various ethnicities, it has been reported to be especially prevalent in the Danish population and haplotype analysis revealed that it is a Danish founder mutation (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). Finally, a mini-gene splicing assay has shown that this mutation causes aberrant splicing (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.