Submissions for variant NM_144997.7(FLCN):c.1379_1380del (p.Leu460fs)

dbSNP: rs1064793128

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485073	SCV000565011	pathogenic	not provided	2017-08-30	criteria provided, single submitter	clinical testing	The c.1379_1380delTC variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dube syndrome (Schmidt et al., 2005; Toro et al., 2008; Miura et al., 2015; Furuya et al., 2016). The deletion causes a frameshift starting with codon Leucine 460, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Leu360GlnfsX25. 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.1379_1380delTC to be pathogenic.
Ambry Genetics	RCV000492502	SCV000580760	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	clinical testing	The c.1379_1380delTC pathogenic mutation, located in coding exon 9 of the FLCN gene, results from a deletion of two nucleotides at nucleotide positions 1379 to 1380, causing a translational frameshift with a predicted alternate stop codon (p.L460Qfs*25). This mutation has been reported in multiple individuals with clinical features of Birt-Hogg-Dubé syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33; Toro JR et al. J. Med. Genet. 2008 Jun; 45(6):321-31; Maffé A et al. Clin. Genet. 2011 Apr; 79(4):345-54; Furuya M et al. Am J Surg Pathol, 2012 Apr;36:589-600; Miura K et al. Surg Case Rep. 2015 Dec;1(1):17; Castellucci R et al. Urologia, 2017 Apr;84:116-120; Sager RA et al. Oncotarget, 2018 Apr;9:22220-22229). Of note, this alteration is also designated as c.1834delTC and c.1834-5delTC 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.
Invitae	RCV000702300	SCV000831149	pathogenic	Birt-Hogg-Dube syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu460Glnfs*25) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418213). This variant is also known as 1834delTC or 1834-5delTC. This premature translational stop signal has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 18234728, 20618353, 22441547, 26943385, 27220747, 28009417). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Mayo Clinic Laboratories, Mayo Clinic	RCV000485073	SCV002522525	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	PP4, PM2, PS4_moderate, PVS1
Myriad Genetics, Inc.	RCV000702300	SCV004019229	pathogenic	Birt-Hogg-Dube syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000702300	SCV004195370	pathogenic	Birt-Hogg-Dube syndrome	2023-03-02	criteria provided, single submitter	clinical testing