NM_144997.7(FLCN):c.1597_1598del (p.Gln533fs) AND Birt-Hogg-Dube syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001244466.5

Allele description [Variation Report for NM_144997.7(FLCN):c.1597_1598del (p.Gln533fs)]

NM_144997.7(FLCN):c.1597_1598del (p.Gln533fs)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1597_1598del (p.Gln533fs)

HGVS:

NC_000017.11:g.17213798GT[2]
NG_008001.2:g.28387CA[2]
NM_001353229.2:c.1651_1652del
NM_001353230.2:c.1597_1598del
NM_001353231.2:c.1597_1598del
NM_144997.7:c.1597_1598delMANE SELECT
NP_001340158.1:p.Gln551fs
NP_001340159.1:p.Gln533fs
NP_001340160.1:p.Gln533fs
NP_659434.2:p.Gln533fs
LRG_325t1:c.1597_1598del
LRG_325:g.28387CA[2]
NC_000017.10:g.17117111_17117112del
NC_000017.10:g.17117112GT[2]
NM_144997.5:c.1597_1598del
NM_144997.5:c.1597_1598delCA

Protein change:

Q533fs

Links:

dbSNP: rs876660810

NCBI 1000 Genomes Browser:

rs876660810

Molecular consequence:

NM_001353229.2:c.1651_1652del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353230.2:c.1597_1598del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353231.2:c.1597_1598del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144997.7:c.1597_1598del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Mus musculus forkhead box B1 (Foxb1), mRNA
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gi|11693137|ref|NM_022378.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001417688	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20403193, 17028174, 18403135, 18663353, 22977732, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001417688

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

Renal cancer associated with recurrent spontaneous pneumothorax in Birt-Hogg-Dubé syndrome: a case report and review of the literature.

Warwick G, Izatt L, Sawicka E.

J Med Case Rep. 2010 Apr 19;4:106. doi: 10.1186/1752-1947-4-106.

PubMed [citation]

PMID:: 20403193
PMCID:: PMC2862043

Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B.

Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. Epub 2006 Oct 6.

PubMed [citation]

PMID:: 17028174
PMCID:: PMC1592464

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001417688.3

#	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 results in a frameshift in the FLCN gene (p.Gln533Glufs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the FLCN protein and extend the protein by 20 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with Birt-Hogg-Dub√© syndrome (PMID: 20403193; Invitae). This variant is also known as 2052_2053del. ClinVar contains an entry for this variant (Variation ID: 234040). This variant disrupts the FNIP1/2 interaction domain, which has been shown to be important for AMPK-mediated mTOR signaling pathways (PMID: 17028174, 18403135, 18663353, 22977732). While functional studies have not been performed to directly test the effect of this variant on FLCN protein function, this suggests that disruption of this region of the protein may be causative of disease. This variant disrupts a region of the FLCN protein in which other variant(s) (p.Trp553Arg) have been determined to be pathogenic (Invitae; external communications). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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