FLCN

Gene Facts

• HGNC Symbol: FLCN (HGNC:27310)
• HGNC Name: folliculin
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: BHD, MGC17998, MGC23445, DENND8B
• %HI: 46.02
• pLI: 0.99
• LOEUF: 0.49
• Cytoband: 17p11.2
• Genomic Coordinates:

  GRCh37/hg19:	chr17:17115526-17140482
  GRCh38/hg38:	chr17:17212212-17237330

• MANE Select Transcript: NM_144997.7 ENST00000285071.9
• Function: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:34381247, PubMed:32612235, PubMed:36103527, PubMed:37079666). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the non-canonical mTORC1 signaling cascade controlling the Mi... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-26180
• ClinGen Curation ID: CCID:007144
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 01/11/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Birt-Hogg-Dubé Syndrome

HI Evidence

• PUBMED: 22146830
  Houweling et al. 2011 presented the clinical data of 115 FLCN mutation carriers from 35 Birt–Hogg–Dubé (BDH) families. In two of the families with clinical BHD but without a mutation in the coding region of FLCN, a deletion of exon 1 was observed. Exon 1 is the first of three non-coding exons. The exact size and the effects of these deletions remain to be determined.
• PUBMED: 20413710
  Kunogi et al. 2010 studied 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography and qPCR were applied for mutation screening. An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations, which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3'-end of the FLCN gene including exons 12 and 13 (13/25=52.0%).
• PUBMED: 21412933
  Benhammou et al. 2011 identified six intragenic deletions and one intragenic duplication in 47% (7/15) of unrelated BHDS families and characterized 5 of 7 breakpoints. Data from this study confirm that, in addition to frameshift, missense, nonsense and splice-site mutations, BHDS can be caused by intragenic CNVs.
• PUBMED: 35639097
  Savatt, et al (2022). Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. P/LP truncating FLCN variants were identified in 35 individuals, including 14 unique variants: 5 nonsense, 5 frameshift, and 2 splicing variants.
• PUBMED: 35637701
  Zhou, et al (2022). 287 Chinese patients with BHD from 143 families described in 31 references were included in this systematic review. A total of 120 variants were included in the supplementary table, including 22 nonsense, 63 frameshift, and 9 splicing variants, and 11 large deletions within the gene.
• PUBMED: 33927747
  Cai et al. (2021). This paper reported a family with BHD patient. A novel FLCN intragenic deletion spanning exons 10-14 was identified by NGS and MLPA in four affected members. Bidirectional sequencing of the PCR products confirmed an 8,384 bp deletion encompassing exons 10–14 (chr17: 17113559-17121942).

• HI Evidence Comments: Deletion and loss-of-function mutation of FLCN is associated with autosomal dominant Birt–Hogg–Dubé syndrome (BHDS), characterized by predisposition to develop cutaneous manifestations, pulmonary cysts, pneumothorax, and various types of renal tumors. Typical age of onset occurs in the third or fourth decade. Genotype-phenotype associations are not well-established in BHDS. Penetrance is considered to be high. The majority of mutations reported in BHDS are sequence-level alterations. Intragenic, exon-level deletions and duplications have also been reported in BHDS. Reports of focal, whole gene FLCN deletion are lacking. Note that FLCN resides within a segmental duplication-flanked region of 17p11.2 that is recurrently deleted in Smith-Magenis syndrome, however the contribution of FLCN haploinsufficiency in SMS in unknown.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: As yet, focal duplication of FLCN has not been reported in association with clinical phenotypes; therefore the triplosensitivity score is 0. PMID 21429933: Pichert et al., 2011 report three patients with non-focal duplication of FLCN. The smallest duplication was 412 kb, encompassing FLCN and 4 other genes (overlapping NTSM). Intragenic duplications that presumably result in functional inactivation of FLCN have been reported in BHDS (PMIDs 21412933 and 12204536).