ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1579C>T (p.Arg527Ter) (rs879255683)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239694 SCV000298092 likely pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000479484 SCV000566466 pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted FLCN c.1579C>T at the cDNA level and p.Arg527Ter (R527X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been found to segregate with disease in at least one family with Birt-Hogg-Dub? syndrome (Schmidt 2005, Vocke 2005). In addition, expressed FLCN protein with this variant did not bind to HA-FNIP1 (Baba 2006). Based on current evidence, we consider FLCN Arg527Ter to be pathogenic.
Invitae RCV000239694 SCV000632853 pathogenic Multiple fibrofolliculomas 2019-11-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the FLCN mRNA at codon 527 (p.Arg527*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 53 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with disease in two families with Birt-Hogg-Dub syndrome (BHDS) (PMID: 15852235, Invitae). This variant is also known as 2034C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 253258). 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. This variant was described as unable to bind FNIP1, however, the data was not shown (PMID: 17028174). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001012272 SCV001172704 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-03 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000239694 SCV001445864 pathogenic Multiple fibrofolliculomas 2019-05-30 criteria provided, single submitter clinical testing This nonsense mutation is found in the last exon of FLCN; the functional consequence of this variant is therefore difficult to predict. However, two pathogenic nonsense variants further 3' to this variant have been reported in individuals affected with Birt-Hogg-Dube Syndrome (PMID: 19802896, 28558743). This variant has been previously reported as a heterozygous change in individuals with Birt-Hogg-Dube Syndrome (PMID: 15852235). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1579C>T (p.Arg527Ter) variant is classified as Pathogenic.

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