ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230001 SCV000291442 pathogenic Multiple fibrofolliculomas 2019-07-05 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-Dub 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 2018-11-20 criteria provided, single submitter clinical testing This duplication of one nucleotide in FLCN is denoted c.347dupA at the cDNA level and p.Leu117AlafsX16 (L117AfsX16) at the protein level. The normal sequence, with the base that is duplicated in braces, is ACCCCC[A]GCTC. The duplication causes a frameshift which changes a Leucine to an Alanine at codon 117, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. FLCN c.347dupA, also reported as c.802insA using alternate nomenclature, has been reported in several individuals meeting clinical diagnostic criteria for Birt-Hogg-Dubé syndrome (Toro 2008, Palmirotta 2008, Maffé 2011, Pradella 2013) and is considered pathogenic.
Ambry Genetics RCV000492339 SCV000580748 pathogenic Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.

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