NM_144997.7(FLCN):c.1607_1622del (p.Leu536fs) AND Birt-Hogg-Dube syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 17, 2022
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:: RCV000806769.4

Allele description [Variation Report for NM_144997.7(FLCN):c.1607_1622del (p.Leu536fs)]

NM_144997.7(FLCN):c.1607_1622del (p.Leu536fs)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1607_1622del (p.Leu536fs)

HGVS:

NC_000017.11:g.17213776_17213791del
NG_008001.2:g.28401_28416del
NM_001353229.2:c.1661_1676del
NM_001353230.2:c.1607_1622del
NM_001353231.2:c.1607_1622del
NM_144997.7:c.1607_1622delMANE SELECT
NP_001340158.1:p.Leu554fs
NP_001340159.1:p.Leu536fs
NP_001340160.1:p.Leu536fs
NP_659434.2:p.Leu536fs
LRG_325t1:c.1607_1622del
LRG_325t1:c.1607_1622del16
LRG_325:g.28401_28416del
NC_000017.10:g.17117087_17117102del
NC_000017.10:g.17117090_17117105del
NM_144997.5:c.1607_1622del
NM_144997.5:c.1607_1622del16

Protein change:

L536fs

Links:

dbSNP: rs1597574088

NCBI 1000 Genomes Browser:

rs1597574088

Molecular consequence:

NM_001353229.2:c.1661_1676del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353230.2:c.1607_1622del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353231.2:c.1607_1622del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144997.7:c.1607_1622del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000946786	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17028174, 18403135, 18663353, 22977732, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000946786

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2022)

germline

clinical testing

PubMed (5)
[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

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

Identification and characterization of a novel folliculin-interacting protein FNIP2.

Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, Schmidt LS.

Gene. 2008 May 31;415(1-2):60-7. doi: 10.1016/j.gene.2008.02.022. Epub 2008 Mar 4.

PubMed [citation]

PMID:: 18403135
PMCID:: PMC2727720

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000946786.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu536Argfs*10) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the FLCN protein. ClinVar contains an entry for this variant (Variation ID: 651413). For these reasons, this variant has been classified as Pathogenic. 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. 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.

#	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: Oct 8, 2024

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