chr17-17216394-T-TG

Position:

• chr17-17216394-T-TG

Variant summary

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

The ENST00000285071.9(FLCN):​c.1285_1286insC​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. H429H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: FLCN ENST00000285071.9 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]

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/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1285_1286insC	p.His429ProfsTer27	frameshift_variant	11/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1285_1286insC	p.His429ProfsTer27	frameshift_variant	11/14	1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-1088dup		intron_variant		3		ENSP00000464276

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

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 07, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FLCN: PVS1, PP1:Strong, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	The FLCN c.1285dupC; 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-Dube 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-Dube syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID: 12204536. Sattler EC et al. Delayed diagnosis of Birt-Hogg-Dube syndrome due to marked intrafamilial clinical variability: a case report. BMC Med Genet. 2018 Mar 16;19(1):45. PMID: 29548312. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 30, 2024	PP1, PP4, PS3_supporting, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Birt-Hogg-Dube syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Apr 22, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 12, 2024	Criteria applied: PVS1,PS4_MOD,PS3_SUP,PP1,PP4 -

Familial spontaneous pneumothorax Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2022	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-Dubé 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 28, 2021

- -

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;