Submissions for variant NM_144997.7(FLCN):c.1285del (p.His429fs)

dbSNP: rs80338682

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082625	SCV000114667	pathogenic	not provided	2013-12-20	criteria provided, single submitter	clinical testing
UCLA Clinical Genomics Center, UCLA	RCV000003531	SCV000255372	pathogenic	Birt-Hogg-Dube syndrome	2014-06-10	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000003531	SCV000298075	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082625	SCV000321665	pathogenic	not provided	2022-04-29	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: 21401403, 18234728, 27220747, 22446046, 21937013, 23155228, 28695430, 23741947, 25326637, 25827758, 26334087, 20522427, 22148047, 25519458, 26659639, 27734835, 19802896, 24346394, 15852235, 19562744, 27229674, 18505456, 23223565, 28326182, 28151982, 28839995, 12204536, 12471204, 34229741, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003531	SCV000549477	pathogenic	Birt-Hogg-Dube syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His429Thrfs*39) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 12471204, 15852235, 20301695, 25519458, 25827758). This variant is also known as c.1733delC. ClinVar contains an entry for this variant (Variation ID: 3364). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492709	SCV000580727	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-03	criteria provided, single submitter	clinical testing	The c.1285delC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Tfs*39). This mutation has been reported in the literature in multiple individuals with features consistent with Birt-Hogg-Dubé syndrome, including fibrofolliculomas, spontaneous pneumothorax, lung cysts, benign renal cysts, and renal tumors (Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Whitworth J et al. JAMA Oncol. 2016 Mar;2:373-9; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157). Of note, this alteration is also designated as c.1733delC 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000082625	SCV001157602	pathogenic	not provided	2023-12-06	criteria provided, single submitter	clinical testing	The FLCN c.1285delC; p.His429fs variant (rs80338683), also known as 1733delC, is reported in several individuals and families with Birt-Hogg-Dube syndrome (Khoo 2002, Ray 2015, Whitworth 2016, Xing 2017), and is reported as pathogenic in ClinVar (Variation ID: 3364). 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 Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. PMID: 12471204. Ray A et al. Genetic analysis of familial spontaneous pneumothorax in an Indian family. Lung. 2015 Jun;193(3):433-8. PMID: 25827758. Whitworth J et al. Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA Oncol. 2016 Mar;2(3):373-9. PMID: 26659639. Xing H et al. Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax. J Thorac Dis. 2017 Jul;9(7):1967-1972. PMID: 28839995.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000082625	SCV001450180	pathogenic	not provided	2016-01-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003531	SCV002026410	pathogenic	Birt-Hogg-Dube syndrome	2021-10-14	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000082625	SCV002551328	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000003531	SCV002581052	pathogenic	Birt-Hogg-Dube syndrome	2022-07-20	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000003531	SCV002761435	pathogenic	Birt-Hogg-Dube syndrome	2020-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003321	SCV002809352	pathogenic	Familial spontaneous pneumothorax; Nonpapillary renal cell carcinoma; Colorectal cancer; Birt-Hogg-Dube syndrome 1	2024-01-30	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000082625	SCV004026244	pathogenic	not provided	2021-08-10	criteria provided, single submitter	clinical testing	PVS1, PP5, PP1, BP5
Myriad Genetics, Inc.	RCV000003531	SCV004188074	pathogenic	Birt-Hogg-Dube syndrome	2023-07-07	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	RCV004566678	SCV004199786	pathogenic	Birt-Hogg-Dube syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000082625	SCV004218920	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	The FLCN c.1285del (p.His429Thrfs*39) variant (also known as 1733delC) alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. In the published literature, this variant has been reported in multiple individuals with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 28839995 (2017), 27734835 (2017), 26659639 (2016), 25827758 (2015), 25519458 (2014), 18234728 (2008)). The frequency of this variant in the general population, 0.000012 (3/245324 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082625	SCV004226843	pathogenic	not provided	2024-09-05	criteria provided, single submitter	clinical testing	PP1, PP4, PM2_moderate, PVS1
OMIM	RCV000003531	SCV000023689	pathogenic	Birt-Hogg-Dube syndrome	2009-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000003531	SCV000041591	not provided	Birt-Hogg-Dube syndrome		no assertion provided	literature only
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000003531	SCV004032350	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390636	SCV004120100	pathogenic	FLCN-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The FLCN c.1285delC variant is predicted to result in a frameshift and premature protein termination (p.His429Thrfs*39). This is a common reoccurring variant reported in individuals and families with Birt-Hogg-Dubé syndrome (Table 1, Khoo et al. 2002. PubMed ID: 12471204; Fontcuberta et al. 2011. PubMed ID: 21401403; Radzikowska E et al. 2021. PubMed ID: 34229741). This variant is reported in 3 of ~245,000 alleles in gnomAD; However, the quality of this data is questionable and should be interpreted with caution. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3364/). Frameshift variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.