17-17219126-C-CTTCTGTACTCTCTGGCAACACAGGGGCT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_144997.7(FLCN):c.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA(p.Gly319SerfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E318E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FLCN
NM_144997.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: -0.0560

Publications

4 publications found

Variant links:

Genes affected

FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FLCN Gene-Disease associations (from GenCC):

Birt-Hogg-Dube syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Birt-Hogg-Dube syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
familial spontaneous pneumothorax
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
renal carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-17219126-C-CTTCTGTACTCTCTGGCAACACAGGGGCT is Pathogenic according to our data. Variant chr17-17219126-C-CTTCTGTACTCTCTGGCAACACAGGGGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 96493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLCN	NM_144997.7	MANE Select	c.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA	p.Gly319SerfsTer80	frameshift	Exon 9 of 14	NP_659434.2
FLCN	NM_001353229.2		c.981_1008dupAGCCCCTGTGTTGCCAGAGAGTACAGAA	p.Gly337SerfsTer80	frameshift	Exon 11 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA	p.Gly319SerfsTer80	frameshift	Exon 10 of 15	NP_001340159.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA	p.Gly319SerfsTer80	frameshift	Exon 9 of 14	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	TSL:1	n.149-100_149-73dupAGCCCCTGTGTTGCCAGAGAGTACAGAA		intron	N/A	ENSP00000394249.3
FLCN	ENST00000577591.1	TSL:2	n.-51_-24dupAGCCCCTGTGTTGCCAGAGAGTACAGAA		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Mar 18, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshift variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in several Birt-Hogg-Dube (BHD) syndrome affected families (PMIDs: 15852235 (2005), 12204536 (2002)). Based on the available information, this variant is classified as pathogenic.

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23757202, 12204536, 11836379, 15852235, 18234728, 19802896, 19788617, 26402642, 21937013, 19562744)

Oct 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM2_moderate, PVS1

Birt-Hogg-Dube syndrome

Pathogenic:4

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 18, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly319Serfs*80) 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 Birt-Hogg-Dub√© (BHD) syndrome, and multiple fibrofolliculomas (PMID: 12204536, 19802896, 26402642). It has also been observed to segregate with disease in related individuals. This variant is also known as c.923_950dup and 1378-1405dup. ClinVar contains an entry for this variant (Variation ID: 96493). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.

Jul 06, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

Familial spontaneous pneumothorax

Pathogenic:1

Mar 16, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FLCN c.927_954dup28 (p.Gly319SerfsX80) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.1389C>G (p.Tyr463X) has been classified as pathogenic by our laboratory. The variant was absent in 121372 control chromosomes (ExAC). The variant, c.927_954dup28, also known as c.1378_1405dup, has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (PMS2 c.2186_2187delTC, p.Leu729fsX6). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 10, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thec.927_954dup28pathogenic mutation, located in codingexon6 of theFLCNgene, results from a duplication of 28 nucleotides between positions 927 and 954 causing a translationalframeshiftwith a predicted alternate stopcodon. This alteration has been reported as a recurrent mutation in families clinically diagnosed with Birt-Hogg-Dubé syndrome (Schmidt LS et al.Abstract O-27.Fam. Cancer2011 May; 10Suppl3:S103-16). This mutation was also reported in a 56 year old man with multiple fibrofolliculomas (Wang J et al. Genet. Med. 2015 Sep [epub ahead of print]). Inaddition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med. 2008;10:294).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.056

Mutation Taster

=14/186

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over