VCV000003364.46 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(22)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 3364 Accession: VCV000003364.46

Type and length

Deletion, 1 bp

Location

Cytogenetic: 17p11.2 17: 17216395 (GRCh38) [ NCBI UCSC ] 17: 17119709 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 8, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_144997.7:c.1285del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_659434.2:p.His429fs	frameshift
NM_144997.7:c.1285delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_001353229.2:c.1339del	NP_001340158.1:p.His447fs	frameshift
NM_001353230.2:c.1285del	NP_001340159.1:p.His429fs	frameshift
NM_001353231.2:c.1285del	NP_001340160.1:p.His429fs	frameshift
NM_144997.5:c.1285del		frameshift
NM_144997.6:c.1285del
NM_144997.6:c.1285delC
NC_000017.11:g.17216402del
NC_000017.10:g.17119716del
NG_008001.2:g.25794del
LRG_325:g.25794del
LRG_325t1:c.1278del	LRG_325p1:p.His429Thrfs

... more HGVS ... less HGVS

Protein change

H447fs, H429fs

Other names

p.His429Thrfs*39

Canonical SPDI

NC_000017.11:17216394:GGGGGGGG:GGGGGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 607273.0002 dbSNP: rs80338682 ClinGen: CA224154 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FLCN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2403	2523

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Birt-Hogg-Dube syndrome	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV000003531.23
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000082625.27
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 10, 2021	RCV000492709.5
Birt-Hogg-Dube syndrome Colorectal cancer Familial spontaneous pneumothorax Nonpapillary renal cell carcinoma Potocki-Lupski syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 12, 2022	RCV002496246.2
FLCN-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 26, 2024	RCV003390636.6
Birt-Hogg-Dube syndrome 1	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2024	RCV004566678.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 20, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114667.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 19, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FLCN Number of individuals with the variant: 10 Sex: mixed
Pathogenic (Jan 19, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450180.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 13
Pathogenic (Jul 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581052.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PP1_STR, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: male
Pathogenic (Mar 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	None (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761435.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Jul 18, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Birt-Hogg-Dube Syndrome Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000298075.2 First in ClinVar: Aug 29, 2016 Last updated: Dec 24, 2022 Comment: Clinical Testing	Number of individuals with the variant: 53
Pathogenic (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026244.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PP5, PP1, BP5
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004188074.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Mar 02, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004218920.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (12) PubMed: 20301695‚ 26659639‚ 25326637‚ 19562744‚ 12204536‚ 12471204‚ 18234728‚ 15852235‚ 28839995‚ 27734835‚ 25519458‚ 25827758 Comment: The FLCN c.1285del (p.His429Thrfs39) variant (also known as 1733delC) alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN … (more) The FLCN c.1285del (p.His429Thrfs39) 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. (less)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551328.7 First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024
Pathogenic (Jun 10, 2014)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Multiple fibrofolliculomas (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255372.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Age: 60-69 years Sex: male Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Oct 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002026410.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021	Comment: _x000D_ Criteria applied: PVS1, PS4
Pathogenic (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer Birt-Hogg-Dube syndrome 1 Nonpapillary renal cell carcinoma Familial spontaneous pneumothorax Potocki-Lupski syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809352.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321665.10 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Mar 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226843.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 34229741 Comment: PP1, PP4, PM2, PVS1 Number of individuals with the variant: 3
Pathogenic (Jan 24, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Birt-Hogg-Dube syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000549477.9 First in ClinVar: Aug 29, 2016 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 28492532‚ 15852235‚ 12471204‚ 20301695‚ 25519458‚ 25827758 Comment: This sequence change creates a premature translational stop signal (p.His429Thrfs39) in the FLCN gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.His429Thrfs39) 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-Dub√© 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. (less)
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157602.2 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 10, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000580727.6 First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 12471204‚ 15852235‚ 18234728‚ 26659639‚ 27734835‚ 28839995 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004199786.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 01, 2009)	no assertion criteria provided Method: literature only	BIRT-HOGG-DUBE SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023689.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2023	Publications: PubMed (2) PubMed: 19562744‚ 12204536 Comment on evidence: Based on the numbering system used by Wei et al. (2009), the 1733delC mutation has been renumbered as 1285delC. See 607273.0001 and Nickerson et al. … (more) Based on the numbering system used by Wei et al. (2009), the 1733delC mutation has been renumbered as 1285delC. See 607273.0001 and Nickerson et al. (2002). The 1285delC mutation, which occurs in exon 11 of the FLCN gene, produces a frameshift and protein truncation. (less)
Pathogenic (Jul 01, 2023)	no assertion criteria provided Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: yes Allele origin: germline	Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine Accession: SCV004032350.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Clinical Features: Pneumothorax (present) , Pulmonary cyst (present) , Abnormality of the skin (absent) , Renal neoplasm (absent)
Pathogenic (Aug 26, 2024)	no assertion criteria provided Method: clinical testing	FLCN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120100.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The FLCN c.1285delC variant is predicted to result in a frameshift and premature protein termination (p.His429Thrfs39). This is a common reoccurring variant reported in individuals … (more) The FLCN c.1285delC variant is predicted to result in a frameshift and premature protein termination (p.His429Thrfs39). 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. (less)
not provided (-)	no classification provided Method: literature only	Birt-Hogg-Dube syndrome Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000041591.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 12204536‚ 15852235‚ 20301695 BookShelf: NBK1522 BookShelf: NBK1522
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Comment:

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.

Comment:

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)

Comment:

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-Dub√© 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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel folliculin gene mutations in Polish patients with Birt-Hogg-Dubé syndrome.	Radzikowska E	Orphanet journal of rare diseases	2021	PMID: 34229741
Birt-Hogg-Dubé Syndrome.	Adam MP	-	2020	PMID: 20301695
Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax.	Xing H	Journal of thoracic disease	2017	PMID: 28839995
Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation.	Rossing M	Journal of human genetics	2017	PMID: 27734835
Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review.	Whitworth J	JAMA oncology	2016	PMID: 26659639
Genetic analysis of familial spontaneous pneumothorax in an Indian family.	Ray A	Lung	2015	PMID: 25827758
Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study.	Benusiglio PR	Orphanet journal of rare diseases	2014	PMID: 25519458
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome.	Wei MH	Human mutation	2009	PMID: 19562744
BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.	Toro JR	Journal of medical genetics	2008	PMID: 18234728
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.	Schmidt LS	American journal of human genetics	2005	PMID: 15852235
Clinical and genetic studies of Birt-Hogg-Dubé syndrome.	Khoo SK	Journal of medical genetics	2002	PMID: 12471204
Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.	Nickerson ML	Cancer cell	2002	PMID: 12204536
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FLCN	-	-	-	-
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Text-mined citations for rs80338682 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338682 ...