Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL3A1 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:2201 | OrphaNet: 91387 | OMIM:120180
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 7.0 7
Kontusaari S et al. 1990 Jul (PMID:2349939); Kontusaari S et al. 1990 Nov (PMID:2243125); Pepin MG et al. 2014 Dec (PMID:24922459); Kuivaniemi H et al. 1990 Jul 15 (PMID:2365710); Proost D et al. 2015 Aug (PMID:25907466); Narcisi P et al. 1993 May 15 (PMID:8098182); Khalique Z et al. 2009 Nov (PMID:19695909); (PMID 2349939: 1 proband (1 point) PMID 2243125: 1 proband (1 point) PMID 24922459: 37/ 1231 probands with vEDS had ortic rupture / dissection in thoracic aorta (=3%). Note all syndromic as part of vascular EDS. (0.1 points each) PMID 2365710: 2/3 had thoracic aortic phenotypes; 1 only minimally syndromic (easy bruising). Points: 2 points PMID 25907466 : 1 proband non syndromic by screening candidate genes. 0.1 PMID 8098182 : syndromic. 24 yr old woman with acrogeria, dissecting aortic aneurysm. Gly1021Glu with functional abnormalities of COL3A1 demonstrated (fibroblasts). 1 points PMID 19695909: 61 year old. Acute type B dissection in non-syndromic man with COL3A1 mutation (& family history of arterial rupture). Splice acceptor mutation. 0.1 point )
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 2.0 2
Kontusaari S et al. 1990 Jul (PMID:2349939); Kontusaari S et al. 1990 Nov (PMID:2243125); (PMIDs 2349939 and 2243125: combined segregations. points 2)
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) 9
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
Nicholls AC et al. 1988 Mar (PMID:3162228); Khalique Z et al. 2009 Nov (PMID:19695909); (Expression: PMID 3162228,19695909: Reduced Col3A1 in subset of patients with haploinsufficiency. Biochemical function: Disrupted Col1 fibrils in knockout mice. Consistent with disease (weakness of aortic wall ( aortic aneurysm / dissection / rupture))
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Kontusaari S et al. 1990 Nov (PMID:2243125); Narcisi P et al. 1993 May 15 (PMID:8098182); (PMID 2243125: Abnormal migration and secretion of Col3A1 from patient cells (fibroblasts) PMID 8098182: Reduced thermal stability of Col3A1 from patient cells)
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Liu X et al. 1997 Mar 4 (PMID:9050868); Smith LB et al. 2011 Apr 1 (PMID:21071432); (PMID: 21071432 : Mouse with partial Col3A1 deletion. Propensity for aortic dissection without hypertension / dilatation - mimics human vEDS vascular phenotype. Penetrance about 28%. PMID:9050868 Col3a1 deletion. Homozygous - 90-95% perinatal lethality. Those surviving had reduced life expectancy due to rupture. Ultrastructural analysis shows collagen 1 fibrils in aortic adventitia.)
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) 6

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 9 6 15 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
03/09/2016
EXPERT CURATION (DATE)
DEFINITIVE
03/14/2016
Assertion made by the Aortopathy working group. Thoracic aortic disease presentation in cases with vascular Ehlers-Danlos syndrome (vEDS) due to pathogenic variants in COL3A1 is rare but affected individuals can present with acute aortic dissections, leading to the classification of COL3A1 in this category. In effect curation was done as a whole for vEDS with thoracic disease.