ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.466_468TTC[1] (p.Phe157del) (rs786203218)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166434 SCV000217229 pathogenic Hereditary cancer-predisposing syndrome 2017-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239623 SCV000298047 likely pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000256108 SCV000321653 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in FLCN is denoted c.469_471delTTC at the cDNA level and p.Phe157del (F157del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTTC[delTTC]ATCA. This variant, also defined as FLCN c.924_926del using alternate nomenclature, has been reported in several individuals and kindreds with features of Birt-Hogg-Dub? syndrome and segregated with disease in multiple families (Ren 2008, Houweling 2011, Byrne 2012, Shvartsbeyn 2012, Radzikowska 2016). An in vitro assay by Nahorski et al. (2011) found that FLCN Phe157del reduced FLCN protein expression and significantly disrupted protein stability. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Phenylalanine amino acid is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect.? Based on current evidence, we consider this variant to be pathogenic.
Invitae RCV000239623 SCV000830120 pathogenic Multiple fibrofolliculomas 2018-06-15 criteria provided, single submitter clinical testing This variant, c.469_471delTTC, results in the deletion of 1 amino acid of the FLCN protein (p.Phe157del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Birt-Hogg-Dubé syndrome (PMID: 22571569, 27906882) and breast cancer (PMID: 28724667). In addition, it has been reported to segregate with pulmonary cysts and pneumothorax in several families (PMID: 18505456, 22146830). This variant is also known as c.924_926del in the literature. ClinVar contains an entry for this variant (Variation ID: 186785). An experimental study has shown that this in-frame deletion significantly disrupts the stability of the FLCN protein (PMID: 21538689). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003541 SCV000023699 pathogenic Pneumothorax, primary spontaneous 2009-09-01 no assertion criteria provided literature only

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