ClinVar Genomic variation as it relates to human health
NM_144997.7(FLCN):c.1177-5_1177-3del
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(6); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_144997.7(FLCN):c.1177-5_1177-3del
Variation ID: 228691 Accession: VCV000228691.27
- Type and length
-
Microsatellite, 3 bp
- Location
-
Cytogenetic: 17p11.2 17: 17216506-17216508 (GRCh38) [ NCBI UCSC ] 17: 17119820-17119822 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Apr 15, 2024 Feb 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_144997.7:c.1177-5_1177-3del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_144997.7:c.1177-5_1177-3delCTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001353229.2:c.1231-5_1231-3del intron variant NM_001353230.2:c.1177-5_1177-3del intron variant NM_001353231.2:c.1177-5_1177-3del intron variant NM_144997.5:c.1177-5_1177-3delCTC NC_000017.11:g.17216508GGA[1] NC_000017.10:g.17119822GGA[1] NG_008001.2:g.25678CTC[1] LRG_325:g.25678CTC[1] LRG_325t1:c.1177-5_1177-3del - Protein change
- Other names
- -
- Canonical SPDI
- NC_000017.11:17216505:GAGGAGGA:GAGGA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
FLCN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2292 | 2412 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 19, 2018 | RCV000217604.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 15, 2022 | RCV000217238.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 6, 2022 | RCV000255836.6 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Feb 13, 2024 | RCV000239690.17 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157399.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The FLCN c.1177-5_1177-3delCTC variant (rs767671406) is reported in the literature in individuals with Birt-Hogg-Dube syndrome (Bartram 2017, Furuya 2016, Johannesma 2014, Kunogi Okura 2013, Kunogi … (more)
The FLCN c.1177-5_1177-3delCTC variant (rs767671406) is reported in the literature in individuals with Birt-Hogg-Dube syndrome (Bartram 2017, Furuya 2016, Johannesma 2014, Kunogi Okura 2013, Kunogi 2010), and it has been shown to co-segregate with disease (Kunogi Okura 2013). Functional analyses demonstrate that this intronic variant causes exon skipping ultimately leading to a truncated and destabilized protein (Bartram 2017). This variant is reported by multiple laboratories in ClinVar (Variation ID: 228691). It is found in the general population with a low overall allele frequency of 0.001% (3/243776 alleles) in the Genome Aggregation Database. Computational algorithms also predict that the variant has an impact on the nearby canonical splice acceptor (Alamut v.2.10), consistent with functional studies. Based on available information, this variant is considered pathogenic. REFERENCES Bartram MP et al. Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC Med Genet. 2017 May 12;18(1):53. Furuya M et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. Clin Genet. 2016 Nov;90(5):403-412. Johannesma PC et al. Spontaneous pneumothorax as indicator for Birt-Hogg-Dube syndrome in paediatric patients. BMC Pediatr. 2014 Jul 3;14:171. Kunogi Okura M et al. Pneumothorax developing for the first time in a 73-year-old woman diagnosed with Birt-Hogg-Dube syndrome. Intern Med. 2013;52(21):2453-5. Kunogi M et al. Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010 Apr;47(4):281-7. (less)
|
|
Likely pathogenic
(Jan 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube syndrome 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271788.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2021 |
Comment:
The c.1177-5_1177-3delCTC variant in FLCN has been reported in at least 2 individuals with Birt-Hogg-Dube syndrome (BHDS) and 6 individuals with suspected BHDS and segregated … (more)
The c.1177-5_1177-3delCTC variant in FLCN has been reported in at least 2 individuals with Birt-Hogg-Dube syndrome (BHDS) and 6 individuals with suspected BHDS and segregated with clinical features of the disease in 3 affected individuals from 2 families (Kunogi 2010 PMID: 20413710, Kunogi Okura 2013 PMID: 24190151, Johannesma 2014 PMID: 24994497, Furuya 2016 PMID: 27220747, Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369, Liu 2017 PMID: 28558743). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 228691) and has identified in 0.005% (1/21382) of Finnish and 0.002% (2/111570) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 3 nucleotides in the 3' splice region. In vitro minigene splicing assays functional studies support an impact on splicing, through exon 11 skipping, that leads to a truncated or absent protein (Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Birt-Hogg-Dube syndrome. ACMG/AMP Criteria applied: PS4_Strong, PM2_Supporting, PP1, PS3_Moderate. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Oct 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube syndrome 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580505.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
|
|
Pathogenic
(Jul 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273659.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.1177-5_1177-3delCTC intronic pathogenic mutation is located 3 nucleotides before coding exon 8 of the FLCN gene. This variant results from a deletion of 3 … (more)
The c.1177-5_1177-3delCTC intronic pathogenic mutation is located 3 nucleotides before coding exon 8 of the FLCN gene. This variant results from a deletion of 3 nucleotides (CTC) from positions c.1177-5 to c.1177-3. This variant has been reported in multiple unrelated individuals with features of Birt-Hogg-Dube (BHD) syndrome, or symptoms consistent with BHDS (Lim DH et al. Hum Mutat. 2010 Jan;31(1):E1043-51; Okura M et al. Intern. Med. 2013;52(21):2453-5; Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Bartram MP et al. BMC Med. Genet. 2017 May;18:53) and has been found to segregate with disease (Okura M et al. Intern Med. 2013;52(21):2453-5; Ambry Internal Data). In addition, rtPCR and mini-gene splicing assays both indicate that this alteration results in exon skipping and a transcript lacking coding exon 8 (Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Rossing M et al. J. Hum. Genet. 2017 Feb;62(2):151-157; Bartram MP et al. BMC Med. Genet. 2017 May;18(1):53). Internal RNA studies have also demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Jul 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube Syndrome
Affected status: yes
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000298072.2
First in ClinVar: Aug 29, 2016 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 14
|
|
Pathogenic
(Aug 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321661.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Non-canonical splice site variant demonstrated to result in loss of function (Kunogi et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Non-canonical splice site variant demonstrated to result in loss of function (Kunogi et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28558743, 19802896, 27220747, 24190151, 24994497, 27734835, 11100034, 28499369, 29357828, 31625278, 20413710) (less)
|
|
Likely pathogenic
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188030.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20413710]. This variant has been reported in multiple individuals with … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20413710]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 27734835, 24190151, 24994497, 31615547, 28499369]. (less)
|
|
Pathogenic
(Oct 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226887.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_moderate, PP4, PM2, PS3, PS4_moderate
Number of individuals with the variant: 2
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000632828.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 10 of the FLCN gene. It does not directly change the encoded amino acid sequence of the FLCN protein. … (more)
This sequence change falls in intron 10 of the FLCN gene. It does not directly change the encoded amino acid sequence of the FLCN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs767671406, gnomAD 0.005%). This variant has been observed in individuals with Birt‚ÄìHogg‚ÄìDubv© syndrome (PMID: 19802896, 20413710, 24190151, 24994497, 27220747, 27734835). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27734835, 28499369; Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Feb 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Birt-Hogg-Dube syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813407.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: FLCN c.1177-5_1177-3delCTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: FLCN c.1177-5_1177-3delCTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence via minigene assay confirmed by Sanger sequencing, that the variant results in skipping of exon 11 and fusion of exon 10 (in frame) to exon 12 which generates a frameshift and premature stop codon (p.T393Sfs33*) (e.g. Bartram_2017). The variant allele was found at a frequency of 1.2e-05 in 248662 control chromosomes. c.1177-5_1177-3delCTC has been reported in the literature in multiple heterozygous individuals affected with Birt-Hogg-Dube Syndrome including in families with multiple affected individuals (e.g. KunogiOkura_2013, Bartram_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing that FLCN protein levels in the presence of the variant are severely reduced in vitro and in patient tumor samples and peritoneal metastasis (e.g. Batram_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28499369, 24190151). ClinVar contains an entry for this variant (Variation ID: 228691). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jul 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Birt-Hogg-Dube syndrome 1
Affected status: yes
Allele origin:
germline
|
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine
Accession: SCV004032423.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Clinical Features:
Pneumothorax (present) , Pulmonary cyst (present) , Abnormality of the skin (present) , Renal neoplasm (absent)
|
|
click to load more click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population. | Lagerstedt-Robinson K | PloS one | 2022 | PMID: 35176117 |
The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome. | Guo T | Annals of translational medicine | 2020 | PMID: 33313181 |
Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants. | Liu K | Orphanet journal of rare diseases | 2019 | PMID: 31615547 |
Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome. | Liu Y | Orphanet journal of rare diseases | 2017 | PMID: 28558743 |
Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. | Bartram MP | BMC medical genetics | 2017 | PMID: 28499369 |
Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation. | Rossing M | Journal of human genetics | 2017 | PMID: 27734835 |
Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. | Furuya M | Clinical genetics | 2016 | PMID: 27220747 |
Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. | Johannesma PC | BMC pediatrics | 2014 | PMID: 24994497 |
Pneumothorax developing for the first time in a 73-year-old woman diagnosed with Birt-Hogg-Dubé syndrome. | Kunogi Okura M | Internal medicine (Tokyo, Japan) | 2013 | PMID: 24190151 |
Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. | Kunogi M | Journal of medical genetics | 2010 | PMID: 20413710 |
A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. | Lim DH | Human mutation | 2010 | PMID: 19802896 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. | Liu V | Journal of the American Academy of Dermatology | 2000 | PMID: 11100034 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
click to load more click to collapse |
Text-mined citations for rs767671406 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.