Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MAT2A : Familial thoracic aortic aneurysm and aortic dissection

HGNC:6904 | OrphaNet: 91387 | OMIM:601468
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 2.0 2
Guo DC et al. 2015 Jan 8 (PMID:25557781); (DNA from two affected family members was used for whole-exome sequencing to identify a rare variant c.1031A>C; (p.Glu344Ala) in MAT2A. Variant is predicted to be damaging by six in silico algorithms + CADD score of 24. Segregates with aortic disease. Proband point=1.5 Additional screening of individuals with familial thoracic aortic aneurysm and aortic dissection (FTAAD) (78 exome sequencing and 447 Sanger for all MAT2A exons) identified p.Arg356His variant in one individual. However same individual harbors a rare missense variant in ACTA2. This variant was predicted to be damaging buy six bioinformatic tools. The functionality of the mutations were tested in zebrafish by morpholino KO and coinjection with human wild type and mutant mRNA . Points=0.5 )
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 4.0 4
Guo DC et al. 2015 Jan 8 (PMID:25557781); (Linkage analysis of thoracic aortic disease with the MAT2A variant (c.1031A>C) in TAA059 generated a two-point LOD score of 2.31. )
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 0.0 0
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 0.0
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Guo DC et al. 2015 Jan 8 (PMID:25557781); (Morpholino KO in zebrafish leading to pericardial edema and rescue by human MAT2a. Points=2 (model system) +2 (rescue). )
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
07/03/2016
EXPERT CURATION (DATE)
LIMITED
07/03/2016
Assertion made by the Aortopathy working group. Recent gene - no additional mutations in a cohort from unpublished data on >400 patients - points subtracted giving it a final limited classification.