rs398124530

Variant names:

• chr17-17214990-C-T
• rs398124530
• NM_144997.7:c.1533G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.1533G>A​(p.Trp511*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.17
• Publications: 10 publications found

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17214990-C-T is Pathogenic according to our data. Variant chr17-17214990-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96478.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.1533G>A	p.Trp511*	stop_gained	Exon 13 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1533G>A	p.Trp511*	stop_gained	Exon 13 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*367G>A		non_coding_transcript_exon_variant	Exon 9 of 12	1		ENSP00000394249.3
ENSG00000264187	ENST00000427497.3	n.*367G>A		3_prime_UTR_variant	Exon 9 of 12	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-2500C>T		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:3

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

- -

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

- -

Nov 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the FLCN gene (p.Trp511*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 69 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Birt-Hogg-Dubé syndrome (BHDS) (PMID: 20413710). ClinVar contains an entry for this variant (Variation ID: 96478). A different truncation downstream of this variant (p.Arg527*) has been determined to be pathogenic (PMID: 15852235, 17028174). This suggests that deletion of this region of the FLCN protein is causative of disease. FLCN protein has been shown to interact with FNIP1 and FNIP2 proteins which bind AMPK to influence mTOR signaling pathway (PMID: 26334087, 17028174, 18403135, 18663353). Experimental evidence expressing a series of C-terminal deletion mutants has localized the minimal interaction region to amino acid residues 517-579 (PMID: 17028174, 18403135), which is expected to be completely disrupted by this truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 11, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W511* pathogenic mutation (also known as c.1533G>A), located in coding exon 10 of the FLCN gene, results from a G to A substitution at nucleotide position 1533. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This alteration occurs at the 3' terminus of theFLCN gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12%, 69 amino acids, of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, as well as several other alterations predicted to result in C-terminal truncation, have been detected in multiple individuals who have a personal and/or family history that is consistent with FLCN-associated disease (Kunogi M et al. J Med Genet, 2010 Apr;47:281-7; Liu Y et al. Orphanet J Rare Dis, 2017 05;12:104; Liu K et al. Orphanet J Rare Dis, 2019 10;14:223; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 23, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong, PP4_Strong, PM2_Supporting c.1533G>A creates a premature translational stop signal, p.(Trp511*), in the exon 13 (of 14) of the FLCN gene resulting in protein truncation in a gene disease.According to MANE select, the encoded transcript has 579 aa, so this mutation is expected to cause the loss of 68 aa (affecting folliculin domain), which supossed 11,7% of the protein (PVS1_Strong). This variant is not present in population databases (gnomAD no frequency) (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing. This variant has been reported in the ClinVar (6x pathogenic) and in LOVD (1x pathogenic) databases. This variant has been identified in several families with individuals affected with Birt-Hogg-Dubé syndrome (PMID: 28558743, PMID: 31615547, PMID: 20413710 and internal data)(PP4_Strong). Based on currently available information, the variant c.1533G>A is classified as a likely pathogenic variant according to ACMG guidelines. -

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:17p11.2 microduplication syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Sep 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 21, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
Vest4		0.94
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398124530; hg19: chr17-17118304;