NM_144997.7:c.1285dupC

Variant names:

• chr17-17216394-T-TG
• rs80338682
• NM_144997.7:c.1285dupC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_144997.7(FLCN):​c.1285dupC​(p.His429ProfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,612,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 O:1
• Conservation: PhyloP100: 7.28

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]

ENSG00000264187 (HGNC:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-17216394-T-TG is Pathogenic according to our data. Variant chr17-17216394-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 3363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1285dupC	p.His429ProfsTer27	frameshift_variant	Exon 11 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1285dupC	p.His429ProfsTer27	frameshift_variant	Exon 11 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*119dupC		non_coding_transcript_exon_variant	Exon 7 of 12	1		ENSP00000394249.3
ENSG00000264187	ENST00000427497.3	n.*119dupC		3_prime_UTR_variant	Exon 7 of 12	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-1088dupG		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151768 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1460472 Hom.: 0 Cov.: 31 AF XY: 0.0000771 AC XY: 56 AN XY: 726548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000907

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74252

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:12 Other:1

Jul 01, 2023

Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Birt-Hogg-Dube syndrome (MIM#135150) and primary spontaneous pneumothorax (MIM#173600). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least 10 NMD-predicted likely pathogenic/pathogenic variants in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The c.1285dupC variant, along with the c.1285delC variant, are the most common pathogenic variants and have been reported in 20%-24% of families with Birt-Hogg-Dube syndrome (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 08, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2020

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.1285dupC (p.His429ProfsX27) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 245324 control chromosomes (gnomAD). c.1285dupC has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005, Hoshika_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant has an impact on protein function (Hoshika_2016). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 07, 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. -

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 29, 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.His429Profs*27) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé (BHD) syndrome (PMID: 12204536, 12471204, 17496196, 20522427). It has also been observed to segregate with disease in related individuals. This variant is also known as 1733insC, 1740dupC, and 1277insC. ClinVar contains an entry for this variant (Variation ID: 3363). For these reasons, this variant has been classified as Pathogenic. -

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

- -

not provided Pathogenic:10

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLCN c.1285dup; p.His429ProfsTer27 variant (rs80338682), also known as 9C, 1733insC, 1740dupC, and 1277insC, is a well-known pathogenic variant that occurs in the mutational sequence hot-spot of eight cytosine nucleotides in exon 11 on the FLCN gene. Both c.1285delC and c.1285dupC have been reported in several patients diagnosed with Birt-Hogg-Dube syndrome (Khoo 2002, Lee 2019, Nahorski 2011, Nickerson 2002, Sattler 2018). The c.1285dupC variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 3363). This variant causes a frameshift by duplicating 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 Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. PMID: 12471204. Lee JH et al. Birt-Hogg-Dubé syndrome in Korean: clinicoradiologic features and long term follow-up. Korean J Intern Med. 2019 Jul;34(4):830-840. PMID: 30360018. Nahorski MS et al. Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat. 2011 Aug;32(8):921-9. PMID: 21538689. Nickerson ML et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID: 12204536. Sattler EC et al. Delayed diagnosis of Birt-Hogg-Dubé syndrome due to marked intrafamilial clinical variability: a case report. BMC Med Genet. 2018 Mar 16;19(1):45. PMID: 29548312. -

Jun 26, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 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. In the published literature, the variant has been reported in several individuals and families with Birt-Hogg-Dube Syndrome (PMIDs: 12204536 (2002), 12471204 (2002), 17496196 (2007), 18505456 (2008), 26028485 (2015), 27220747 (2016), 27734835 (2017), 27905298 (2016), 29357828 (2018), 29548312 (2018), and 30360018 (2019)). Functional studies found that this variant significantly impaired FLCN protein stability and function (PMIDs: 21538689 (2011) and 27905298 (2016)). Based on the available information, this variant is classified as pathogenic. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLCN: PVS1, PP1:Strong, PS4:Moderate, PP4 -

Feb 06, 2024

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PS3_supporting, PS4_moderate, PVS1 -

Aug 09, 2022

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; Published functional studies demonstrate a damaging effect: inactivates gene expression, disrupts protein stability, inhibits tumor suppression, and down-regulates multiple genes involved in TGF-beta signaling (Hong et al., 2010a; Hong et al., 2010b; Nahorski et al., 2011); Also known as 1733insC; This variant is associated with the following publications: (PMID: 21209915, 23784378, 23416984, 12204536, 27229674, 28152038, 12471204, 21538689, 22146830, 23995526, 24346394, 20573232, 25594584, 19850877, 20618353, 18505456, 27220747, 27734835, 28558743, 28690286, 28151982, 29357828, 30360018, 29548312, 28724667, 26387484, 26028485, 28869776, 22148048, 20522427, 31019283, 32782288, 33726816, 34008892, 30696655) -

Apr 11, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome 1 Pathogenic:2

Apr 22, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLCN c.1285dup (p.His429ProfsTer27) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. The variant is located in the polycytosine tract in exon 11 and has been reported in several individuals with Birt-Hogg-Dubé syndrome (PMID: 26028485; 29548312; 30360018; 30696655; 34540968; 35664771). In summary, this variant meets criteria to be classified as pathogenic. -

Nov 12, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD,PS3_SUP,PP1,PP4 -

Familial spontaneous pneumothorax Pathogenic:2

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1285dupC;p.(His429Profs*27) is a null frameshift variant (NMD) in the FLCN gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3363; PMID: 12471204; PMID: 20522427; PMID: 17496196; PMID: 12204536)PS4_moderate. This variant is not present in population databases (rs80338682- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 09, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 02, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1285dupC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a duplication of C at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Pfs*27). This recurrent mutation has been reported in multiple families affected with Birt-Hogg-Dub&eacute; syndrome and was shown to result in significant impairment of FLCN protein stability and function (Nickerson ML et al. Cancer Cell. 2002 Aug;2:157-64; Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Nahorski MS et al. Hum. Mutat. 2011 Aug;32:921-9; Nishida C et al. Respir. Med. 2015 Jul;109:923-5; Furuya M et al. Clin. Genet. 2016 Nov;90:403-412; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157; Lee JH et al. Korean J. Intern. Med. 2018 Oct). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

FLCN-related disorder Pathogenic:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FLCN c.1285dupC variant is predicted to result in a frameshift and premature protein termination (p.His429Profs*27). This variant has been reported to be causative for Birt-Hogg-Dubé syndrome (Khoo et al. 2002. PubMed ID: 12471204, listed as 1733insC; Nahorski et al. 2011. PubMed ID: 21538689; Luijten et al. 2013. PubMed ID: 23784378). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD. However, the quality of data at this genomic position is questionable and allele frequency data should be interpreted with caution. This variant been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3363/). Frameshift variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:Potocki-Lupski syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Sep 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338682; hg19: chr17-17119708;