NM_144997.7(FLCN):c.1285del (p.His429fs) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Feb 6, 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:: RCV000082625.26

Allele description [Variation Report for NM_144997.7(FLCN):c.1285del (p.His429fs)]

NM_144997.7(FLCN):c.1285del (p.His429fs)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1285del (p.His429fs)

Other names:

p.His429Thrfs*39

HGVS:

NC_000017.10:g.17119709del
NC_000017.11:g.17216402del
NG_008001.2:g.25794del
NM_001353229.2:c.1339del
NM_001353230.2:c.1285del
NM_001353231.2:c.1285del
NM_144997.7:c.1285delMANE SELECT
NP_001340158.1:p.His447fs
NP_001340159.1:p.His429fs
NP_001340160.1:p.His429fs
NP_659434.2:p.His429Thrfs
NP_659434.2:p.His429fs
LRG_325t1:c.1278del
LRG_325:g.25794del
LRG_325p1:p.His429Thrfs
NC_000017.10:g.17119709del
NC_000017.10:g.17119716del
NC_000017.10:g.17119716del
NC_000017.10:g.17119716delG
NM_144997.4:c.1285delC
NM_144997.5:c.1278delC
NM_144997.5:c.1285del
NM_144997.5:c.1285delC
NM_144997.6:c.1285del
NM_144997.6:c.1285delC
NM_144997.7:c.1285delCMANE SELECT
p.[His429Thrfs*39]

Protein change:

H429fs

Links:

OMIM: 607273.0002; dbSNP: rs80338682

NCBI 1000 Genomes Browser:

rs80338682

Molecular consequence:

NM_001353229.2:c.1339del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353230.2:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353231.2:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144997.7:c.1285del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000114667	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 20, 2013)	germline	clinical testing	Citation Link,
SCV000321665	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 29, 2022)	germline	clinical testing	Citation Link,
SCV001157602	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 25, 2023)	germline	clinical testing	Citation Link,
SCV001450180	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 19, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002551328	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004026244	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004218920	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 2, 2023)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 20301695, 26659639, 25326637, 19562744, 12204536, 12471204, 18234728, 15852235, 28839995, 27734835, 25519458, 25827758, 26467025
SCV004226843	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34229741, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	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
not provided	germline	yes	13	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	13	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Birt-Hogg-Dubé Syndrome.

Sattler EC, Steinlein OK.

2006 Feb 27 [updated 2020 Jan 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301695

Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review.

Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD, Maher ER.

JAMA Oncol. 2016 Mar;2(3):373-9. doi: 10.1001/jamaoncol.2015.4771. Review.

PubMed [citation]

PMID:: 26659639

See all PubMed Citations (15)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000114667.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	not provided

#	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		10	not provided	not provided	not provided

From GeneDx, SCV000321665.10

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

Description

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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21401403, 18234728, 27220747, 22446046, 21937013, 23155228, 28695430, 23741947, 25326637, 25827758, 26334087, 20522427, 22148047, 25519458, 26659639, 27734835, 19802896, 24346394, 15852235, 19562744, 27229674, 18505456, 23223565, 28326182, 28151982, 28839995, 12204536, 12471204, 34229741, 31589614)

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157602.2

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

Description

The FLCN c.1285delC; p.His429fs variant (rs80338683), also known as 1733delC, is reported in several individuals and families with Birt-Hogg-Dube syndrome (Khoo 2002, Ray 2015, Whitworth 2016, Xing 2017), and is reported as pathogenic in ClinVar (Variation ID: 3364). This variant causes a frameshift by deleting a single nucleotide, 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 Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. PMID: 12471204. Ray A et al. Genetic analysis of familial spontaneous pneumothorax in an Indian family. Lung. 2015 Jun;193(3):433-8. PMID: 25827758. Whitworth J et al. Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA Oncol. 2016 Mar;2(3):373-9. PMID: 26659639. Xing H et al. Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax. J Thorac Dis. 2017 Jul;9(7):1967-1972. PMID: 28839995.

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450180.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	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	germline	yes	not provided	not provided	not provided		13	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002551328.6

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV004026244.1

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

Description

PVS1, PP5, PP1, BP5

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004218920.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The FLCN c.1285del (p.His429Thrfs*39) variant (also known as 1733delC) alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. In the published literature, this variant has been reported in multiple individuals with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 28839995 (2017), 27734835 (2017), 26659639 (2016), 25827758 (2015), 25519458 (2014), 18234728 (2008)). The frequency of this variant in the general population, 0.000012 (3/245324 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226843.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

PP1, PP4, PM2, PVS1

#	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		3	not provided	not provided	not provided

Last Updated: May 7, 2024

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