ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1285dup (p.His429fs) (rs80338682)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508113 SCV000603726 pathogenic not specified 2017-02-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130568 SCV000185439 pathogenic Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000003529 SCV000298076 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082626 SCV000114668 pathogenic not provided 2013-04-11 no assertion criteria provided clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000003529 SCV000883143 pathogenic Multiple fibrofolliculomas 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000082626 SCV000329354 pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing This duplication of one nucleotide in FLCN is denoted c.1285dupC at the cDNA level and p.His429ProfsX27 (H429PfsX27) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCCCCCCC[dupC]ACGT. Using alternate nomenclature, this variant would be defined as FLCN 1733insC. The duplication causes a frameshift which changes a Histidine to a Proline at codon 429, and creates a premature stop codon at position 27 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.1285dupC has been reported in multiple individuals with a clinical diagnosis of Birt-Hogg-Dub? syndrome (BHD), and is the pathogenic variant most often identified in individuals with BHD (Nickerson 2002, Hasumi 2009, Furuya 2015, Rossing 2017). In vitro functional studies show this variant inactivates gene expression, disrupts protein stability, inhibits tumor suppression, and down-regulates multiple genes involved in TGF-beta signaling (Hong 2010a, Hong 2010b, Nahorski 2011). Based on the currently available evidence, we consider this variant to be pathogenic.
GeneReviews RCV000003529 SCV000041592 pathologic Multiple fibrofolliculomas 2008-09-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000003530 SCV000919364 pathogenic Pneumothorax, primary spontaneous 2018-10-01 criteria provided, single submitter clinical testing Variant summary: FLCN c.1285dupC (p.His429ProfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1389C>G, p.Tyr463X). The variant allele was found at a frequency of 5.4e-05 in 241096 control chromosomes. c.1285dupC has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome and is a common pathogenic variant. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000003529 SCV000261689 pathogenic Multiple fibrofolliculomas 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His429Profs*27) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with Birt-Hogg-Dubé (BHD) syndrome (PMID: 12471204, 20522427, 17496196, 12204536). This variant is also known as 1733insC, 1740dupC, and 1277insC in the literature. ClinVar contains an entry for this variant (Variation ID: 3363). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003529 SCV000023687 pathogenic Multiple fibrofolliculomas 2010-06-01 no assertion criteria provided literature only
OMIM RCV000003530 SCV000023688 pathogenic Pneumothorax, primary spontaneous 2010-06-01 no assertion criteria provided literature only

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