GeneBe

rs398124542

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_144997.7(FLCN):​c.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA​(p.Gly319SerfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FLCN
NM_144997.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: -0.0560
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-17219126-C-CTTCTGTACTCTCTGGCAACACAGGGGCT is Pathogenic according to our data. Variant chr17-17219126-C-CTTCTGTACTCTCTGGCAACACAGGGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 96493.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
FLCNNM_144997.7 linkc.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA p.Gly319SerfsTer80 frameshift_variant Exon 9 of 14 ENST00000285071.9 NP_659434.2 Q8NFG4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkc.927_954dupAGCCCCTGTGTTGCCAGAGAGTACAGAA p.Gly319SerfsTer80 frameshift_variant Exon 9 of 14 1 NM_144997.7 ENSP00000285071.4 Q8NFG4-1
ENSG00000264187ENST00000427497.3 linkn.149-100_149-73dupAGCCCCTGTGTTGCCAGAGAGTACAGAA intron_variant Intron 4 of 11 1 ENSP00000394249.3 J3QW42
FLCNENST00000577591.1 linkn.-51_-24dupAGCCCCTGTGTTGCCAGAGAGTACAGAA upstream_gene_variant 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461870
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727238
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Apr 16, 2021
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; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 23757202, 12204536, 11836379, 15852235, 18234728, 19802896, 19788617, 26402642, 21937013, 19562744) -

Mar 18, 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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in several Birt-Hogg-Dube (BHD) syndrome affected families (PMIDs: 15852235 (2005), 12204536 (2002)). Based on the available information, this variant is classified as pathogenic. -

Oct 17, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1_strong, PM2_moderate, PVS1 -

Jul 10, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Pathogenic:4
Sep 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 16, 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.Gly319Serfs*80) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé (BHD) syndrome, and multiple fibrofolliculomas (PMID: 12204536, 19802896, 26402642). It has also been observed to segregate with disease in related individuals. This variant is also known as c.923_950dup and 1378-1405dup. ClinVar contains an entry for this variant (Variation ID: 96493). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). 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

- -

Jul 06, 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. -

Familial spontaneous pneumothorax Pathogenic:1
Mar 16, 2018
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.927_954dup28 (p.Gly319SerfsX80) 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. A truncation downstream of this position, c.1389C>G (p.Tyr463X) has been classified as pathogenic by our laboratory. The variant was absent in 121372 control chromosomes (ExAC). The variant, c.927_954dup28, also known as c.1378_1405dup, has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (PMS2 c.2186_2187delTC, p.Leu729fsX6). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Mar 10, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

<span style="font-family:arial,sans-serif; font-size:10pt">The<span style="font-family:arial,sans-serif">c.927_<span style="font-family:arial,sans-serif; font-size:10pt">954dup28<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">pathogenic mutation, located in codingexon6 of the<span style="font-family:arial,sans-serif; font-size:10pt">FLCN<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">gene, results from a duplication of 28 nucleotides between positions 927 and 954 causing a translationalframeshiftwith a predicted alternate stopcodon. This alteration has been reported as a recurrent mutation in families clinically diagnosed with Birt-Hogg-Dub&eacute; syndrome (Schmidt LS et al.Abstract O-27.<span style="font-family:arial,sans-serif">Fam. Cancer2011 May; 10Suppl3:S103-16). This mutation was also reported in a 56 year old man with multiple fibrofolliculomas (Wang J et al. Genet. Med. 2015 Sep [epub ahead of print]). Inaddition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.<span style="font-family:arial,sans-serif">Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs398124542; hg19: chr17-17122440; API