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 2019-04-30 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17028174, 19802896, 15852235, 15956655, 29357828, 28191890, 31589614)
Invitae RCV000239694 SCV000632853 pathogenic Multiple fibrofolliculomas 2020-10-28 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-Dubé 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 pathogenic Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing The p.R527* variant (also known as c.1579C>T), located in coding exon 11 of the FLCN gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 11. This stop codon occurs at the 3' terminus of FLCN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 53 amino acids of the protein. This alteration as well as several other alterations predicted to result in C-terminal truncation have been detected in multiple individuals who meet clinical diagnostic criteria for Birt-Hogg-Dube Syndrome (Schmidt LS et al. Am. J. Hum. Genet., 2005 Jun;76:1023-33; Lim DH et al. Hum. Mutat. 2010 Jan;31(1):E1043-51; Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
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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