Variant 17-17219187-GCTTT-G details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

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 17-17219187-GCTTT-G is Pathogenic according to our data. Variant chr17-17219187-GCTTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 96492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219187-GCTTT-G is described in Lovd as [Pathogenic]. Variant chr17-17219187-GCTTT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.890_893del	p.Glu297AlafsTer25	frameshift_variant	9/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.890_893del	p.Glu297AlafsTer25	frameshift_variant	9/14	1	NM_144997.7	ENSP00000285071	P1	Q8NFG4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251428

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461770

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	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 a significant frequency in large population cohorts (Lek et al., 2016); Identified in patients with Birt-Hogg-Dub syndrome in published literature (Kluger 2010, Dow 2016, Sprague 2016); This variant is associated with the following publications: (PMID: 19785621, 27470329, 27356891, 29138412, 27643397, 18794106) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 16, 2021	This frameshift variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113764 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 19785621 (2010), 27470329 (2016), 27643397 (2016)) as well as an individual with renal cell carcinoma (RCC) (PMID: 18794106 (2008)), and an individual with colorectal cancer (PMID: 27356891 (2016)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	The FLCN c.890_893delAAAG; p.Glu297fs variant (rs398124541), also known as 1388_1391delAAAG, is reported in individuals with Birt-Hogg-Dube syndrome (Dow 2016, Kluger 2010, Sprague 2016, Woodward 2008) and classified as pathogenic in ClinVar (Variation ID: 96492). This variant is only observed on 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, 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 Dow E et al. Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex. Am J Med Genet A. 2016 Dec;170(12):3323-3326. Kluger N et al. Birt-Hogg-Dube syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010 Mar;162(3):527-37. Sprague J et al. Birt-Hogg-Dube Syndrome Presenting as a Nevus Comedonicus-Like Lesion in an 8-Year-Old Boy. Pediatr Dermatol. 2016 Sep;33(5):e294-5. Woodward ER et al. Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin Cancer Res. 2008 Sep 15;14(18):5925-30. -

Birt-Hogg-Dube syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	This sequence change creates a premature translational stop signal (p.Glu297Alafs*25) 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 present in population databases (rs398124541, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dub_x0001_e (BHD) syndrome, colorectal cancer, and/or renal cell cancer with pulmonary features (PMID: 18794106, 19785621, 27356891, 27470329, 27643397). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1388_1391delAAAG. ClinVar contains an entry for this variant (Variation ID: 96492). 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, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

FLCN-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

The FLCN c.890_893delAAAG variant is predicted to result in a frameshift and premature protein termination (p.Glu297Alafs*25). In the literature, this variant is also referred to as c.1388_1391delAAAG (p.Glu297Alafs*321). This variant has been reported in individuals with Birt-Hogg-Dub syndrome (Kluger et al. 2009. PubMed ID: 19785621; Dow et al. 2016. PubMed ID: 27643397; Sprague et al. 2016. PubMed ID: 27470329). This variant, in the heterozygous state, was also reported in an individual who presented with isolated renal cell carcinoma and later developed pulmonary features (Patient 2, Woodward et al. 2008. PubMed ID: 18794106) and in another individual with colorectal cancer (Dobbins et al. 2016. PubMed ID: 27356891). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17122501-GCTTT-G). Frameshift variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.890_893delAAAG pathogenic mutation, located in coding exon 6 of the FLCN gene, results from a deletion of 4 nucleotides at nucleotide positions 890 to 893, causing a translational frameshift with a predicted alternate stop codon (p.E297Afs*25). This mutation was reported in a 25-year-old female with renal cell carcinoma (Woodward ER et al. Clin. Cancer Res., 2008 Sep;14:5925-30) and has also been reported in a Birt-Hogg-Dubé syndrome (BHDS) kindred, that presented with extensive multi-organ system involvement, including fibrofolliculomas, acrochordons, oral papules, lentigines, lipomas, lung cysts, thyroid nodules, cafe-au-lait spots, kidney cysts, rectal papules, endobrachyoesphagus, pneumothorax, colonic adenomatous polyps and atypical mole syndrome (Kluger N et al. Br. J. Dermatol., 2010 Mar;162:527-37). A case report described an 8-year-old boy found to carry this alteration, who presented with nevus comedonicus-like lesion present since birth and had family history of BHDS in his mother, who had been affected with numerous fibrofolliculomas on the face, multiple lung cysts and had a history of spontaneous pneumothorax (Sprague J et al. Pediatr Dermatol, 2016 Jul [Epub ahead of print]). This alteration has also been found in one patient from a cohort of patients with early-onset (at or before 55 years-old) familial (including at least one first degree relative) colorectal cancer, who had no personal or family history of renal cancer (Dobbins SE et al. Fam. Cancer, 2016 Jun [Epub ahead of print]). Note that this alteration is also referred to as c.1388_1391delAAAG and c.1345_1348delAAAG 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

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Splicing

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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

Below is the list of publications found by LitVar. It may be empty.

17-17219187-GCTTT-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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