NM_144997.7(FLCN):c.346C>T (p.Gln116Ter) AND Birt-Hogg-Dube syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 29, 2023
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:: RCV000239717.7

Allele description [Variation Report for NM_144997.7(FLCN):c.346C>T (p.Gln116Ter)]

NM_144997.7(FLCN):c.346C>T (p.Gln116Ter)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.346C>T (p.Gln116Ter)

HGVS:

NC_000017.11:g.17226226G>A
NG_008001.2:g.15963C>T
NM_001353229.2:c.346C>T
NM_001353230.2:c.346C>T
NM_001353231.2:c.346C>T
NM_144606.7:c.346C>T
NM_144997.7:c.346C>TMANE SELECT
NP_001340158.1:p.Gln116Ter
NP_001340159.1:p.Gln116Ter
NP_001340160.1:p.Gln116Ter
NP_653207.1:p.Gln116Ter
NP_659434.2:p.Gln116Ter
LRG_325t1:c.346C>T
LRG_325:g.15963C>T
LRG_325p1:p.Gln116*
NC_000017.10:g.17129540G>A
NM_144997.5:c.346C>T
NP_659434.2:p.Gln116*
p.[Gln116*]

Protein change:

Q116*

Links:

dbSNP: rs398124536

NCBI 1000 Genomes Browser:

rs398124536

Molecular consequence:

NM_001353229.2:c.346C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001353230.2:c.346C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001353231.2:c.346C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_144606.7:c.346C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_144997.7:c.346C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000298044	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,
SCV000756951	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15852235, 18234728, 30580288, 28492532
SCV004186031	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Nov 29, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000298044

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,

SCV000756951

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004186031

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Nov 29, 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	yes	1	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

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 (4)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000298044.2

#	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 Invitae, SCV000756951.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Gln116*) 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 clinical features of Birt-Hogg-Dub√© syndrome (PMID: 18234728, 30580288). ClinVar contains an entry for this variant (Variation ID: 96484). 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., SCV004186031.1

#	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 termination codon and is 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: Mar 30, 2024

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Relating variation to medicine