Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FLCN : Birt-Hogg-Dube syndrome

HGNC:27310 | MONDO_0007607
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 12 10
Nickerson ML et al. 2002 Aug (PMID:12204536);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.5
0.5
So SY et al. 2009 Jul (PMID:19659657);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
3
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
1
Hudon V et al. 2010 Mar (PMID:19843504);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Nickerson ML et al. 2002 Aug (PMID:12204536);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Hudon V et al. 2010 Mar (PMID:19843504); Okimoto K et al. 2004 Feb 17 (PMID:14769940);
Cell culture model 1 0 - 2 1
Hudon V et al. 2010 Mar (PMID:19843504);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1
Hudon V et al. 2010 Mar (PMID:19843504);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
06/04/2018
EXPERT CURATION (DATE)
Definitive
06/04/2018
EVIDENCE SUMMARY
There has been sufficient amount of evidence published associating the FLCN gene with Birt-Hogg-Dube syndrome (BHD) since the gene-disease relationship was first proposed by Nickerson et al. (2002). Plenty of case level studies have been performed with BHD patients that have variants in the FLCN gene. FCLN, which is expressed in skin, lung, and kidney, acts as a general tumor suppressor in human RCC cells in vivo. Knockdown of FLCN in ACHN cells led to the formation of significantly larger tumors and reintroduction of FLCN in 786-0 cells led to a strong decrease in tumor growth. Flcn+/- mice display preneoplastic kidney lesions and tumors and a Nihon rat model of inherited renal cancer with an intragenic Flcn mutation was also established. All of these evidences suggest a definitive relationship between the FLCN gene and Birt-Hogg-Dube syndrome (BHD).