Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FBN1 : Marfan syndrome

HGNC:3603 | MONDO_0007947
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: General Gene Curation
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 6
Dietz HC et al. 1991 Jul 25 (PMID:1852208); Nijbroek G et al. 1995 Jul (PMID:7611299);
Proband with predicted or proven null variant 1.5 0-2 10 2 3 3
Nijbroek G et al. 1995 Jul (PMID:7611299);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
Nijbroek G et al. 1995 Jul (PMID:7611299);
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   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.81 1
Nijbroek G et al. 1995 Jul (PMID:7611299);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.81    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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 Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Verstraeten A et al. 2016 Jun (PMID:26919284);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Quondamatteo F et al. 2002 Dec (PMID:12524050); Zhang H et al. 1995 May (PMID:7744963);
Functional Alteration Patient cells 1 0 - 2 2 1
Granata A et al. 2017 Jan (PMID:27893734);
Non-patient cells 0.5 0 - 1 1 1
Jensen SA et al. 2015 Aug 01 (PMID:25979247);
Models Non-human model organism 2 0 - 4 4 1 2 4
Judge DP et al. 2004 Jul (PMID:15254584);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1 2
Granata A et al. 2017 Jan (PMID:27893734);
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The first report indicating a relationship between the FBN1 gene and autosomal dominant Marfan syndrome was reported by Dietz et al in 1991 (PMID: 1852208). The nomenclature for Marfan syndrome is ascribed to Antoine Marfan, who described a individual with part of the phenotypic features associated with the greater syndrome in 1896 (reviewed in Gott 1998, PMID: 9798380). Marfan syndrome a multisystemic disorder affecting mainly the connective tissue. Marfan comprises a broad phenotypic spectrum and severity and thus represents a continuum of disease (reviewed in Dietz 1991, Marfan GeneReviews, PMID: 20301510). Cardiovascular, ocular, and skeletal phenotypes represent the most common phenotypic manifestations among individuals diagnosed with Marfan syndrome. The cardiovascular phenotypes, including dilatation of the aorta, are the areas that represent the major morbidity and mortality of Marfan syndrome. Over 1800 variants have been identified in FBN1 (Collod-Beroud et al., 2003 PMID: 12938084), including missense, nonsense, frameshift, splice site, small deletions, and large deletions, according to two databases that house variant information: (1) The UMD-FBN1 database (; and (2) the LOVD FBN1 database ( The mechanism for the gene-disease relationship is protein loss of function, as mutation in the the FBN1 protein, fibrillin, results in the inability of the protein to be excreted from cells to help in the formation and stabilization of connective tissue (Sakai et al., 1986, PMID: 3536967). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation. In summary, FBN1 is definitively associated with autosomal dominant Marfan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was reviewed by the FBN1 VCEP with final approval by the ClinGen General GCEP on March 4, 2019 (SOP Version 6).