NM_144997.7(FLCN):c.296del (p.Asp99fs) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 5, 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:: RCV000082634.19

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)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000114676	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 26, 2012)	germline	clinical testing	Citation Link,
SCV000321652	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 15, 2021)	germline	clinical testing	Citation Link,
SCV002522526	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004563593	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 17, 2023)	germline	clinical testing	Citation Link,
SCV005623388	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Jan 5, 2024)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18234728, 15852235, 26467025

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 Eurofins Ntd Llc (ga), SCV000114676.9

#	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	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV000321652.9

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19802896, 18234728, 21937013, 23757202, 29357828, 15852235)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV002522526.3

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

Description

PP4, PM2_moderate, PVS1

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563593.1

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

Description

The FLCN c.296del; p.Asp99ValfsTer31 variant (rs398124534), also published as c.751delA, is reported in the literature in multiple individuals and families affected with Birt-Hogg-Dube syndrome and has been reported to segregate with disease (Mahtani 2021, Schmidt 2005, Toro 2008). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Mahtani K et al. Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases. Hum Hered. 2021;86(1-4):28-33. PMID: 34706366. Schmidt LS et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005 Jun;76(6):1023-33. PMID: 15852235. Toro JR et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31. PMID: 18234728.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV005623388.1

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

Description

The FLCN c.296del (p.Asp99Valfs*31, also known as c.751delA) variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in in individuals with Birt-Hogg-Dube (BHD) syndrome (PMID: 15852235 (2005), 18234728 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

#	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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