Gene Validity Classification Summary

Gene/Disease Pair:

ACTA2 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:130 | OrphaNet: 91387 | OMIM:102620
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 0.0 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 14.0 7
Guo DC et al. 2007 Dec (PMID:17994018); Yoo EH et al. 2010 Summer (PMID:20689142); Morisaki H et al. 2009 Oct (PMID:19639654); Guo DC et al. 2009 May (PMID:19409525); (17994018: 6 probands * 2 points + 8 probands * 1 point Additional PMIDs with probands and segregation data 19409525 19639654 20689142 The curation is not comprehensive as maximum genetic score was reached.)
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 10.0 7
Guo DC et al. 2007 Dec (PMID:17994018); (17994018: All family members with Thoracic aortic aneurysm and dissection (TAAD) also exhibited livedo reticularius. Fine mapping with 31 microsatellite markers on 27 family members on 10q23-24 ->LOD 4.4 (TAAD+ Livedo reticularis) . Analysis of recombinants ->17.2Mb region with candidate gene seq-> ACTA2 R149C. Segregation of this variant with livedo reticularis ->LOD 5.8. 5 points Linkage analysis of TAAD with ACTA2 mutations revealed a LOD score of 4.17 in 14 families of European descent. Points: 5 )
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) 12
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
Lu H et al. 2016 Oct 7 (PMID:27551047); Lu H et al. 2015 Aug 4 (PMID:26153420); (27551047: The R179H mutation in SM α-actin shows severe defects in many facets of actin function including its inability to readily polymerize, with R179H mutant requiring forty-fold more actin to form filaments relative to wild type. 26153420: ACTA2(R258C) mutant actin shows multiple defects, including impaired interaction with myosin, formation of less stable filaments, and enhanced levels of monomer. These defects are likely to decrease cellular force production and initiate aberrant mechanosensing pathways that culminate in the disease. )
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Guo DC et al. 2007 Dec (PMID:17994018); (ACTA2-Antibdy and phalliodin staining of ACTA2 filaments in aortic SMCs derived from two individuals with TAAD who were heterozygous for ACTA2 revealed an absence of ACTA2-containing filaments and an increased pool of unpolymerized ACTA2.)
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 1.0 1
Schildmeyer LA et al. 2000 Nov (PMID:11053242); (Mouse model : Referenced in http://www.informatics.jax.org/allele/MGI:3665248 Defective aortic morphology and highly compromised vascular contractility. )
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) 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)*
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
07/13/2016
EXPERT CURATION (DATE)
DEFINITIVE
09/27/2016
Assertion made by the Aortopathy working group.