NM_144997.7(FLCN):c.1285del (p.His429fs) AND Birt-Hogg-Dube syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Jan 24, 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:: RCV000003531.20

Allele description

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

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

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

Other names:

p.His429Thrfs*39

HGVS:

NC_000017.10:g.17119709del
NC_000017.11:g.17216402del
NG_008001.2:g.25794del
NM_001353229.2:c.1339del
NM_001353230.2:c.1285del
NM_001353231.2:c.1285del
NM_144997.7:c.1285delMANE SELECT
NP_001340158.1:p.His447fs
NP_001340159.1:p.His429fs
NP_001340160.1:p.His429fs
NP_659434.2:p.His429Thrfs
NP_659434.2:p.His429fs
LRG_325t1:c.1278del
LRG_325:g.25794del
LRG_325p1:p.His429Thrfs
NC_000017.10:g.17119709del
NC_000017.10:g.17119716del
NC_000017.10:g.17119716del
NC_000017.10:g.17119716delG
NM_144997.4:c.1285delC
NM_144997.5:c.1278delC
NM_144997.5:c.1285del
NM_144997.5:c.1285delC
NM_144997.6:c.1285del
NM_144997.6:c.1285delC
NM_144997.7:c.1285delCMANE SELECT
p.[His429Thrfs*39]

Protein change:

H429fs

Links:

OMIM: 607273.0002; dbSNP: rs80338682

NCBI 1000 Genomes Browser:

rs80338682

Molecular consequence:

NM_001353229.2:c.1339del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353230.2:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353231.2:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144997.7:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Birt-Hogg-Dube syndrome
Synonyms:: BHD syndrome; 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
SCV000023689	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19562744, 12204536
SCV000041591	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (3) [See all records that cite these PMIDs] 12204536, 15852235, 20301695
SCV000255372	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Pathogenic (Jun 10, 2014)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000298075	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,
SCV000549477	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12471204, 15852235, 20301695, 25519458, 25827758, 28492532
SCV002026410	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581052	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761435	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 13, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004032350	Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	no assertion criteria provided	Pathogenic (Jul 1, 2023)	germline	clinical testing
SCV004188074	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jul 7, 2023)	unknown	clinical testing	Citation Link,
SCV004199786	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	54	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	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
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome.

Wei MH, Blake PW, Shevchenko J, Toro JR.

Hum Mutat. 2009 Sep;30(9):E880-90. doi: 10.1002/humu.21075.

PubMed [citation]

PMID:: 19562744
PMCID:: PMC3234166

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, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS.

Cancer Cell. 2002 Aug;2(2):157-64.

PubMed [citation]

PMID:: 12204536

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000023689.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

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

From GeneReviews, SCV000041591.2

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

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

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255372.2

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

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

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000298075.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	53	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		53	not provided	not provided	not provided

From Invitae, SCV000549477.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002026410.1

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

Description

_x000D_ Criteria applied: PVS1, PS4

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

From MGZ Medical Genetics Center, SCV002581052.1

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

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761435.1

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

#	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		not provided	not provided	not provided	not provided

From Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine, SCV004032350.1

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

From Myriad Genetics, Inc., SCV004188074.1

#	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

From Baylor Genetics, SCV004199786.1

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

#	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 1, 2024

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