Submissions for variant NM_144997.7(FLCN):c.296del (p.Asp99fs)

dbSNP: rs398124534

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082634	SCV000114676	pathogenic	not provided	2012-12-26	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239648	SCV000298042	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082634	SCV000321652	pathogenic	not provided	2021-02-15	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19802896, 18234728, 21937013, 23757202, 29357828, 15852235)
Ambry Genetics	RCV000492350	SCV000580757	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-04	criteria provided, single submitter	clinical testing	The c.296delA pathogenic mutation, located in coding exon 2 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 296, causing a translational frameshift with a predicted alternate stop codon (p.D99Vfs*31). This alteration was previously described in two unrelated families with Birt-Hogg-Dube syndrome, one of which had two family members with fibrofolliculomas and lung cysts, and one of which consisted of an individual with fibrofolliculomas, renal tumors, lung cysts, and multiple pneumothoraces (Toro JR, J. Med. Genet. 2008 Jun; 45(6):321-31; Schmidt LS, Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). Of note, this alteration is also designated as c.751delA in the 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	RCV000239648	SCV000940601	pathogenic	Birt-Hogg-Dube syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp99Valfs*31) 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: 15852235, 18234728). This variant is also known as c.751delA. ClinVar contains an entry for this variant (Variation ID: 96482). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082634	SCV002522526	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Myriad Genetics, Inc.	RCV000239648	SCV003806659	pathogenic	Birt-Hogg-Dube syndrome	2023-01-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000082634	SCV004563593	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	The FLCN c.296del; p.Asp99ValfsTer31 variant (rs398124534), also published as c.751delA, is reported in the literature in multiple individuals and families affected with Birt-Hogg-Dube syndrome and has been reported to segregate with disease (Mahtani 2021, Schmidt 2005, Toro 2008). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it 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: Mahtani K et al. Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases. Hum Hered. 2021;86(1-4):28-33. PMID: 34706366. Schmidt LS et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005 Jun;76(6):1023-33. PMID: 15852235. Toro JR et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31. PMID: 18234728.
GenomeConnect, ClinGen	RCV000239648	SCV000606962	not provided	Birt-Hogg-Dube syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.