NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys) AND Birt-Hogg-Dube syndrome

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jan 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000691604.14

Allele description [Variation Report for NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys)]

NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys)

HGVS:

NC_000017.11:g.17217161G>A
NG_008001.2:g.25028C>T
NM_001353229.2:c.1138C>T
NM_001353230.2:c.1084C>T
NM_001353231.2:c.1084C>T
NM_144997.7:c.1084C>TMANE SELECT
NP_001340158.1:p.Arg380Cys
NP_001340159.1:p.Arg362Cys
NP_001340160.1:p.Arg362Cys
NP_659434.2:p.Arg362Cys
LRG_325t1:c.1084C>T
LRG_325:g.25028C>T
NC_000017.10:g.17120475G>A
NM_144997.5:c.1084C>T
NM_144997.6:c.1084C>T

Protein change:

R362C

Links:

dbSNP: rs557336321

NCBI 1000 Genomes Browser:

rs557336321

Molecular consequence:

NM_001353229.2:c.1138C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353230.2:c.1084C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353231.2:c.1084C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_144997.7:c.1084C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Birt-Hogg-Dube syndrome
Synonyms:: BHD syndrome; Birt Hogg Dubé syndrome
Identifiers:: MONDO: MONDO:0800444; MedGen: C0346010; Orphanet: 122; OMIM: PS135150

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000819390	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 13, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 35441217, 21538689, 33137092, 28492532
SCV001287183	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link,
SCV002030098	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 25, 2021)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195329	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Yngvadottir B, Andreou A, Bassaganyas L, Larionov A, Cornish AJ, Chubb D, Saunders CN, Smith PS, Zhang H, Cole Y, Research Consortium GE, Larkin J, Browning L, Turajlic S, Litchfield K, Houlston RS, Maher ER.

Hum Mol Genet. 2022 Aug 25;31(17):3001-3011. doi: 10.1093/hmg/ddac089.

PubMed [citation]

PMID:: 35441217
PMCID:: PMC9433729

Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability.

Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X, Fenton J, Boora U, Nordenskjöld M, Latif F, Hurst LD, Maher ER.

Hum Mutat. 2011 Aug;32(8):921-9. doi: 10.1002/humu.21519. Epub 2011 Jul 12.

PubMed [citation]

PMID:: 21538689

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819390.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 362 of the FLCN protein (p.Arg362Cys). This variant is present in population databases (rs557336321, gnomAD 0.003%). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 35441217). ClinVar contains an entry for this variant (Variation ID: 485585). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLCN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FLCN function (PMID: 21538689, 33137092). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001287183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV002030098.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004195329.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine