Gene Validity Classification Summary

Gene/Disease Pair:

MFAP5 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:29673 | OrphaNet: 91387 | OMIM:601103
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.0
0
Proband with predicted or proven null variant 1.5 0-2 10 2.0 2
Barbier M et al. 2014 Dec 4 (PMID:25434006); (c.472C>T (p.Arg158∗) segregating with disease in a large 3 generation family. Functional assays showed that c.472C>T leads to pure haploinsufficiency in heterozygous individuals.)
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1.0 1
Barbier M et al. 2014 Dec 4 (PMID:25434006); (c.62G>T (p.Trp21Leu) mutation segregating in a three generation family. Points 1)
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 3.0 3
Barbier M et al. 2014 Dec 4 (PMID:25434006); (Points inferred based on estimated LOD score from combined segregations from two families.)
2 4
1.5 3
1 1.5
   
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 6
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 2.0 2
Gibson MA et al. 1996 Jan 12 (PMID:8557636); Gibson MA et al. 1999 May 7 (PMID:10224057); Combs MD et al. 2013 Oct 4 (PMID:23963447); Lemaire R et al. 2007 Jan 5 (PMID:17099216); Mohamed SA et al. 2009 May 6 (PMID:19652764); Penner AS et al. 2002 Sep 20 (PMID:12122015); (Biochemical Function: PMIDs 8557636 and 10224057: Binding to extracellular matrix components (FBN1-containing microfibrils); adhesion of aortic smooth muscle and other vascular cells to extra cellular matrix (ECM) components and migration. PMID 17099216: Formation of elastin - containing elastic fibres. PMID 23963447: Binding to TGFB1 and TGFB2 - regulation of cell-cell signalling and TGFB pathway. Protein interaction: PMID: 8557636: adhesion to FBN1 - containing microfibrils PMID: 17099216: interaction with elastin PMID 23963447: interaction with TGFB1 and TGFB2 by binding PMID: 12122015: Binding to FBN1. Expression: PMID 19652764: downregulation of expression in aortic wall of patients with acute aortic dissection)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
Barbier M et al. 2014 Dec 4 (PMID:25434006); (Reduced expression of MFAP5 in patient cells; also reduced TGF-Beta signaling in patient tissue (increased TGFB1 and increased pSMAD2/3))
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 1.0 1
Combs MD et al. 2013 Oct 4 (PMID:23963447); (Mouse model: MFAP5-/- mice have no specific CV phenotype; double k/o MFAP 2-/-: MFAP5 -/- mice have age-dependent aortic dilatation )
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

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 6 4 10 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
CALCULATED CLASSIFICATION (DATE)
MODERATE
EXPERT CURATION (DATE)
MODERATE
12/22/2016
Assertion made by the Aortopathy working group.