Submissions for variant NM_144997.7(FLCN):c.946_947del (p.Ser316fs)

dbSNP: rs1597591875

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820246	SCV000960952	pathogenic	Birt-Hogg-Dube syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser316Tyrfs*73) 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 and primary spontaneous pneumothorax (PMID: 27229674, 28069055, 28558743). ClinVar contains an entry for this variant (Variation ID: 662576). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000820246	SCV004175198	pathogenic	Birt-Hogg-Dube syndrome	2023-01-11	criteria provided, single submitter	clinical testing	The FLCN c.946_947del variant is classified as Pathogenic (PVS1, PS4-moderate, PM2) This FLCN c.946_947del variant is located in exon 9/14 and is predicted to cause a shift in the reading frame at codon 316, introducing a premature termination codon 73 amino acids downstream (PVS1). The variant has been reported in two unrelated individuals with Birt-Hogg- Dubé syndrome (PMID: 28558743, 34941164 ), and two other unrelated individuals with a presentation of pneumothorax/suspected Birt-Hogg- Dubé syndrome (PMID: 28069055, 27229674) (PS4-moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1597591875) and in the HGMD database: CD166847. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 662576).
Ambry Genetics	RCV004619431	SCV005115503	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	The c.946_947delAG pathogenic mutation, located in coding exon 6 of the FLCN gene, results from a deletion of two nucleotides at nucleotide positions 946 to 947, causing a translational frameshift with a predicted alternate stop codon (p.S316Yfs*73). This variant was reported in multiple individuals with features consistent with Birt-Hogg-Dube syndrome (Li T et al. Chin J Cancer. 2017 Jan;36:4; Liu Y et al. Orphanet J Rare Dis. 2017 May;12:104; Ren S et al. Medicine (Baltimore). 2021 Dec;100:e28380). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV004792533	SCV005404964	pathogenic	Birt-Hogg-Dube syndrome 1	2024-08-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000820246	SCV004032418	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing