ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1597C>T (p.Gln533Ter) (rs398124532)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082632 SCV000114674 pathogenic not provided 2013-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000082632 SCV000582956 pathogenic not provided 2021-05-27 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 47 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson 2014); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 19802896, 21937013, 17028174, 27535533, 31625278, 31615547)
Invitae RCV000820903 SCV000961639 pathogenic Multiple fibrofolliculomas 2020-09-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FLCN gene (p.Gln533*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome (PMID: 19802896, Invitae). ClinVar contains an entry for this variant (Variation ID: 96480). This variant disrupts the C-terminus of the FLCN protein that contains a large portion of the minimal binding domain for interaction with the FNIP1/2 proteins (residues 517-579) (PMID: 17028174, 18403135), which has been shown to be important for AMPK-mediated mTOR signaling pathways (PMID: 17028174, 18403135, 18663353, 22977732). While functional studies have not been performed to directly test the effect of this variant on FLCN protein function, this suggests that disruption of this region of the protein may be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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