ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1252del (p.Leu418fs) (rs864622651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204355 SCV000261570 pathogenic Multiple fibrofolliculomas 2020-08-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu418Trpfs*50) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Birt-Hogg-Dubé syndrome (PMID: 18234728, 23848572). This variant is also known as 1707delC in the literature. ClinVar contains an entry for this variant (Variation ID: 220767). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000204355 SCV000298073 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000255990 SCV000321664 pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing The c.1252delC variant in the FLCN gene, has been reported previously in association with Birt-Hogg-Dube syndrome (Toro et al., 2008; Raymond et al., 2014). The deletion causes a frameshift starting with codon Leucine 418, changes this amino acid to a Tryptophan residue and creates a premature Stop codon at position 50 of the new reading frame, denoted p.Leu418TrpfsX50. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.1252delC to be pathogenic.
Ambry Genetics RCV000492723 SCV000580744 pathogenic Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing The c.1252delC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1252, causing a translational frameshift with a predicted alternate stop codon (p.L418Wfs*50). This mutation has been identified in multiple patients affected with Birt-Hogg-Dubé syndrome (Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Raymond VM et al. Clin. Endocrinol. (Oxf) 2014 Jun;80:925-7). Of note, this alteration is also designated as 1707delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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