Submissions for variant NM_144997.7(FLCN):c.853C>T (p.Gln285Ter)

dbSNP: rs879255667

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239633	SCV000298062	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239633	SCV000549454	pathogenic	Birt-Hogg-Dube syndrome	2024-08-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln285*) 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: 24393238). ClinVar contains an entry for this variant (Variation ID: 253239). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001582803	SCV001819932	pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Nonsense 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 in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26763815, 23067074, 29357828, 24393238)
Ambry Genetics	RCV002446482	SCV002676763	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The p.Q285* pathogenic mutation (also known as c.853C>T), located in coding exon 5 of the FLCN gene, results from a C to T substitution at nucleotide position 853. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration was identified in a 52-year-old Caucasian male with innumerable facial fibrofolliculomas and trichodiscomas, a history of bilateral spontaneous pneumothoraces, and a unilateral oncocytic/ chromophobe renal tumor with low-grade renal cell carcinoma features; his son reportedly had similar facial skin lesions and history of recurrent pneumothorax (Ge L et al. Med. J. Aust. 2016 Jan;204:28-9). This alteration was also identified in a cohort of Asian Birt-Hogg-Dube syndrome patients (Kumasaka T et al. Histopathology. 2014 Jul;65:100-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582803	SCV005879447	pathogenic	not provided	2024-08-19	criteria provided, single submitter	clinical testing	The FLCN c.853C>T; p.Gln285Ter variant (rs879255667, ClinVar Variation ID: 253239) is reported in the literature in individuals with Birt-Hogg-Dube syndrome (Ge 2016, Kumasaka 2014, Namba 2023). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ge L, Lowe P. Not just a cosmetic problem: facial papules in Birt-Hogg-Dube syndrome. Med J Aust. 2016 Jan 18;204(1):28-9. PMID: 26763815. Kumasaka T et al. Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014 Jul;65(1):100-10. PMID: 24393238. Namba Y et al. Clinical and genetic features of 334 Asian patients with Birt-Hogg-Dube syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax. PLoS One. 2023 Jul 25;18(7):e0289175. PMID: 37490463.
Myriad Genetics, Inc.	RCV005246921	SCV005899321	pathogenic	Birt-Hogg-Dube syndrome 1	2024-10-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000239633	SCV004032408	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing