VCV000253258.17 - ClinVar

NM_144997.7(FLCN):c.1579C>T (p.Arg527Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_144997.7(FLCN):c.1579C>T (p.Arg527Ter)

Variation ID: 253258 Accession: VCV000253258.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p11.2 17: 17213816 (GRCh38) [ NCBI UCSC ] 17: 17117130 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 30, 2016	May 1, 2024	Jan 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_144997.7:c.1579C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_659434.2:p.Arg527Ter	nonsense
NM_001353229.2:c.1633C>T	NP_001340158.1:p.Arg545Ter	nonsense
NM_001353230.2:c.1579C>T	NP_001340159.1:p.Arg527Ter	nonsense
NM_001353231.2:c.1579C>T	NP_001340160.1:p.Arg527Ter	nonsense
NC_000017.11:g.17213816G>A
NC_000017.10:g.17117130G>A
NG_008001.2:g.28373C>T
LRG_325:g.28373C>T
LRG_325t1:c.1579C>T

... more HGVS ... less HGVS

Protein change

R527*, R545*

Other names

Canonical SPDI

NC_000017.11:17213815:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA10586246 dbSNP: rs879255683 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FLCN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2401	2521

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Birt-Hogg-Dube syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 12, 2024	RCV000239694.14
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2019	RCV000479484.3
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 6, 2023	RCV001012272.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jul 18, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Birt-Hogg-Dube Syndrome Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000298092.2 First in ClinVar: Aug 30, 2016 Last updated: Dec 24, 2022 Comment: Clinical Testing	Number of individuals with the variant: 1
Pathogenic (May 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BIRT-HOGG-DUBE SYNDROME Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001445864.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: This nonsense mutation is found in the last exon of FLCN; the functional consequence of this variant is therefore difficult to predict. However, two pathogenic … (more) This nonsense mutation is found in the last exon of FLCN; the functional consequence of this variant is therefore difficult to predict. However, two pathogenic nonsense variants further 3' to this variant have been reported in individuals affected with Birt-Hogg-Dube Syndrome (PMID: 19802896, 28558743). This variant has been previously reported as a heterozygous change in individuals with Birt-Hogg-Dube Syndrome (PMID: 15852235). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1579C>T (p.Arg527Ter) variant is classified as Pathogenic. (less)
Pathogenic (Apr 30, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000566466.4 First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019	Comment: Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more) Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17028174, 19802896, 15852235, 15956655, 29357828, 28191890, 31589614) (less)
Pathogenic (Jan 12, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Birt-Hogg-Dube syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000632853.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 15852235 Comment: This sequence change creates a premature translational stop signal (p.Arg527) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg527) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the FLCN protein. 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-Dub√© syndrome (BHDS) (PMID: 15852235; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 2034C>T. ClinVar contains an entry for this variant (Variation ID: 253258). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 06, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001172704.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 15852235‚ 19802896 Comment: The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 11 of the FLCN gene, results from a C to T substitution at … (more) The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 11 of the FLCN gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 11. This stop codon occurs at the 3' terminus of FLCN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 53 amino acids of the protein. This alteration as well as several other alterations predicted to result in C-terminal truncation have been detected in multiple individuals who meet clinical diagnostic criteria for Birt-Hogg-Dube Syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Lim DH et al. Hum. Mutat. 2010 Jan;31(1):E1043-51; Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004188940.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Comment:

This nonsense mutation is found in the last exon of FLCN; the functional consequence of this variant is therefore difficult to predict. However, two pathogenic nonsense variants further 3' to this variant have been reported in individuals affected with Birt-Hogg-Dube Syndrome (PMID: 19802896, 28558743). This variant has been previously reported as a heterozygous change in individuals with Birt-Hogg-Dube Syndrome (PMID: 15852235). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1579C>T (p.Arg527Ter) variant is classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17028174, 19802896, 15852235, 15956655, 29357828, 28191890, 31589614)

Comment:

This sequence change creates a premature translational stop signal (p.Arg527*) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the FLCN protein. 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-Dub√© syndrome (BHDS) (PMID: 15852235; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 2034C>T. ClinVar contains an entry for this variant (Variation ID: 253258). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 11 of the FLCN gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 11. This stop codon occurs at the 3' terminus of FLCN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 53 amino acids of the protein. This alteration as well as several other alterations predicted to result in C-terminal truncation have been detected in multiple individuals who meet clinical diagnostic criteria for Birt-Hogg-Dube Syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Lim DH et al. Hum. Mutat. 2010 Jan;31(1):E1043-51; Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene.	Lim DH	Human mutation	2010	PMID: 19802896
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.	Schmidt LS	American journal of human genetics	2005	PMID: 15852235

Text-mined citations for rs879255683 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_144997.7(FLCN):c.1579C>T (p.Arg527Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs879255683 ...