ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.347dup (p.Leu117fs) (rs776896550)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230001 SCV000291442 pathogenic Multiple fibrofolliculomas 2019-07-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu117Alafs*16) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs776896550, ExAC 0.002%). This variant has been observed in individuals with skin fibrofolliculomas, lung cysts, and pneumothorax consistent with Birt-Hogg-Dubé syndrome (PMID: 18234728, 23386036, 20618353). This variant is also known as 802insA or 802dupA in the literature. ClinVar contains an entry for this variant (Variation ID: 241922). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000358389 SCV000329351 pathogenic not provided 2019-09-06 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Identified in patients with Birt-Hogg-Dub syndrome in published literature (Toro 2008, Palmirotta 2008, Maff 2011, Pradella 2013); This variant is associated with the following publications: (PMID: 21937013, 23386036, 18234728, 20618353, 18573707, 29357828)
Ambry Genetics RCV000492339 SCV000580748 pathogenic Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing The c.347dupA pathogenic mutation, located in coding exon 2 of the FLCN gene, results from a duplication of A at nucleotide position 347, causing a translational frameshift with a predicted alternate stop codon, p.L117Afs*16. This alteration, also referred to in the literature as c.802insA or c.802dupA, has been reported in multiple individuals meeting clinical diagnostic criteria for Birt-Hogg-Dube syndrome (Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Maffé A et al. Clin. Genet. 2011 Apr;79:345-54; Pradella LM et al. Eur. J. Hum. Genet. 2013 Oct;21:1169-72). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002075 SCV001159913 pathogenic not specified 2018-09-25 criteria provided, single submitter clinical testing The FLCN c.347dupA; p.Leu117fs variant (rs776896550), also known as 802insA or 802dupA in the literature, has been reported in patients with Birt-Hogg-Dube syndrome (Maffe 2011, Pradella 2013, Toro 2008) and is reported as pathogenic in Clinvar (Variation ID: 241922). The variant is found in the general population with an extremely low frequency of 0.00040% (1/246202 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function variants in FLCN are known to be pathogenic (Schmidt 2005). Based on available information, this variant is considered to be pathogenic. REFERENCES Maffe A et al. Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations. Clin Genet. 2011 Apr;79(4):345-54. Pradella LM et al. Where Birt-Hogg-Dube meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. Eur J Hum Genet. 2013 Oct;21(10):1169-72. Schmidt LS et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet. 2005 Jun;76(6):1023-33. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.