ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1533G>A (p.Trp511Ter) (rs398124530)

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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 RCV000082630 SCV000114672 pathogenic not provided 2013-10-21 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239664 SCV000298091 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000239664 SCV000632850 pathogenic Multiple fibrofolliculomas 2018-11-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FLCN gene (p.Trp511*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 69 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Birt-Hogg-Dubé syndrome (BHDS) (PMID: 20413710). ClinVar contains an entry for this variant (Variation ID: 96478). A different truncation downstream of this variant (p.Arg527*) has been determined to be pathogenic (PMID: 15852235, 17028174). This suggests that deletion of this region of the FLCN protein is causative of disease. FLCN protein has been shown to interact with FNIP1 and FNIP2 proteins which bind AMPK to influence mTOR signaling pathway (PMID: 26334087, 17028174, 18403135, 18663353). Experimental evidence expressing a series of C-terminal deletion mutants has localized the minimal interaction region to amino acid residues 517-579 (PMID: 17028174, 18403135), which is expected to be completely disrupted by this truncation. For these reasons, this variant has been classified as Pathogenic.

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