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

dbSNP: rs864622651

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204355	SCV000261570	pathogenic	Birt-Hogg-Dube syndrome	2023-11-07	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. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 18234728, 23848572). This variant is also known as 1707delC. ClinVar contains an entry for this variant (Variation ID: 220767). 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	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000255990	SCV000321664	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18234728, 19802896, 23848572, 21937013, 37273290, 29357828, 33482948)
Ambry Genetics	RCV000492723	SCV000580744	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-12	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; Boland J et al. Perm J, 2020 11;24:1-6). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204355	SCV002555697	pathogenic	Birt-Hogg-Dube syndrome	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: FLCN c.1252delC (p.Leu418TrpfsX50) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249330 control chromosomes (gnomAD). c.1252delC has been reported in the literature in individuals affected with Birt-Hogg-Dube Syndrome (Toro_2008, Raymond_2014, Boland_2020). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000204355	SCV003806647	pathogenic	Birt-Hogg-Dube syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255990	SCV004218917	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 33482948 (2020), 23848572 (2014), 18234728 (2008)). Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255990	SCV004226865	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000204355	SCV004032348	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing