NM_144997.7(FLCN):c.296del (p.Asp99fs) AND Birt-Hogg-Dube syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000239648.13

Allele description [Variation Report for NM_144997.7(FLCN):c.296del (p.Asp99fs)]

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

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

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

Other names:

p.Asp99Valfs*31

HGVS:

NC_000017.11:g.17226276del
NG_008001.2:g.15913del
NM_001353229.2:c.296del
NM_001353230.2:c.296del
NM_001353231.2:c.296del
NM_144606.7:c.296del
NM_144997.7:c.296delMANE SELECT
NP_001340158.1:p.Asp99fs
NP_001340159.1:p.Asp99fs
NP_001340160.1:p.Asp99fs
NP_653207.1:p.Asp99fs
NP_659434.2:p.Asp99fs
LRG_325t1:c.296del
LRG_325:g.15913del
NC_000017.10:g.17129590del
NM_144606.5:c.296delA
NM_144997.5:c.296del
NM_144997.5:c.296delA
NM_144997.6:c.296del
p.[Asp99Valfs*31]

Protein change:

D99fs

Links:

dbSNP: rs398124534

NCBI 1000 Genomes Browser:

rs398124534

Molecular consequence:

NM_001353229.2:c.296del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353230.2:c.296del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353231.2:c.296del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144606.7:c.296del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144997.7:c.296del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Birt-Hogg-Dube syndrome
Synonyms:: Birt Hogg Dubé syndrome
Identifiers:: MONDO: MONDO:0800444; MedGen: C0346010; Orphanet: 122; OMIM: PS135150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000298042	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Jul 18, 2016)	germline	clinical testing	Citation Link,
SCV000606962	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV000940601	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 4, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15852235, 18234728, 28492532
SCV003806659	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jan 19, 2023)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, phenotyping only

Citations

PubMed

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.

Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM.

Am J Hum Genet. 2005 Jun;76(6):1023-33. Epub 2005 Apr 25.

PubMed [citation]

PMID:: 15852235
PMCID:: PMC1196440

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, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM.

J Med Genet. 2008 Jun;45(6):321-31. doi: 10.1136/jmg.2007.054304. Epub 2008 Jan 30. Review.

PubMed [citation]

PMID:: 18234728
PMCID:: PMC2564862

See all PubMed Citations (3)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000298042.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From GenomeConnect, ClinGen, SCV000606962.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	validation		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940601.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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-Dub√© 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV003806659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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