rs80338682

Positions:

• chr17-17216394-TG-T
• chr17-17216394-TG-TGG

Variant summary

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

The ENST00000285071.9(FLCN):​c.1285del​(p.His429ThrfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,434 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FLCN ENST00000285071.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 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-TG-T is Pathogenic according to our data. Variant chr17-17216394-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 3364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17216394-TG-T is described in Lovd as [Pathogenic]. Variant chr17-17216394-TG-T is described in Lovd as [Pathogenic]. Variant chr17-17216394-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1285del	p.His429ThrfsTer39	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.1285del	p.His429ThrfsTer39	frameshift_variant	11/14	1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-1088del		intron_variant		3		ENSP00000464276

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151768 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460666 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151768 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74126

Gnomad4 AFR AF: 0.00

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: 0.0000295

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 13, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.His429Thrfs*39) 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 syndrome (PMID: 12471204, 15852235, 20301695, 25519458, 25827758). This variant is also known as c.1733delC. ClinVar contains an entry for this variant (Variation ID: 3364). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 14, 2021	_x000D_ Criteria applied: PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 20, 2022	- -
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	UCLA Clinical Genomics Center, UCLA	Jun 10, 2014	- -
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	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 02, 2023	The FLCN c.1285del (p.His429Thrfs*39) variant (also known as 1733delC) alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. In the published literature, this variant has been reported in multiple individuals with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 28839995 (2017), 27734835 (2017), 26659639 (2016), 25827758 (2015), 25519458 (2014), 18234728 (2008)). The frequency of this variant in the general population, 0.000012 (3/245324 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Aug 10, 2021	PVS1, PP5, PP1, BP5 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2023	The FLCN c.1285delC; p.His429fs variant (rs80338683), also known as 1733delC, is reported in several individuals and families with Birt-Hogg-Dube syndrome (Khoo 2002, Ray 2015, Whitworth 2016, Xing 2017), and is reported as pathogenic in ClinVar (Variation ID: 3364). 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 Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. PMID: 12471204. Ray A et al. Genetic analysis of familial spontaneous pneumothorax in an Indian family. Lung. 2015 Jun;193(3):433-8. PMID: 25827758. Whitworth J et al. Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA Oncol. 2016 Mar;2(3):373-9. PMID: 26659639. Xing H et al. Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax. J Thorac Dis. 2017 Jul;9(7):1967-1972. PMID: 28839995. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 05, 2024	PP1, PP4, PM2_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21401403, 18234728, 27220747, 22446046, 21937013, 23155228, 28695430, 23741947, 25326637, 25827758, 26334087, 20522427, 22148047, 25519458, 26659639, 27734835, 19802896, 24346394, 15852235, 19562744, 27229674, 18505456, 23223565, 28326182, 28151982, 28839995, 12204536, 12471204, 34229741, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 19, 2016	- -

Birt-Hogg-Dube syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

FLCN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The FLCN c.1285delC variant is predicted to result in a frameshift and premature protein termination (p.His429Thrfs*39). This is a common reoccurring variant reported in individuals and families with Birt-Hogg-Dubé syndrome (Table 1, Khoo et al. 2002. PubMed ID: 12471204; Fontcuberta et al. 2011. PubMed ID: 21401403; Radzikowska E et al. 2021. PubMed ID: 34229741). This variant is reported in 3 of ~245,000 alleles in gnomAD; However, the quality of this data is questionable and should be interpreted with caution. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3364/). 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

Apr 12, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2021

The c.1285delC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Tfs*39). This mutation has been reported in the literature in multiple individuals with features consistent with Birt-Hogg-Dubé syndrome, including fibrofolliculomas, spontaneous pneumothorax, lung cysts, benign renal cysts, and renal tumors (Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Whitworth J et al. JAMA Oncol. 2016 Mar;2:373-9; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157). Of note, this alteration is also designated as c.1733delC in published literature. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;