Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL3A1 : Ehlers-Danlos syndrome, vascular type

HGNC:2201 | MONDO_0017314
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
Proband with predicted or proven null variant 1.5 0-2 10 8 11 10
Schwarze U et al. 2001 Nov (PMID:11577371); Pepin M et al. 2000 Mar 09 (PMID:10706896); Superti-Furga A et al. 1988 May 05 (PMID:2834369); Kuivaniemi H et al. 1990 Jul 15 (PMID:2365710);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7
3
3
Pepin M et al. 2000 Mar 09 (PMID:10706896); Kashizaki F et al. 2013 Feb 01 (PMID:23374456); Baas AF et al. 2017 Feb (PMID:28102592);
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 1.2 1
Baas AF et al. 2017 Feb (PMID:28102592);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
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
0.5
1
Gelse K et al. 2003 Nov 28 (PMID:14623400);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Superti-Furga A et al. 1988 May 05 (PMID:2834369);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Müller GA et al. 2012 Feb (PMID:22038052);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 6 4
Liu X et al. 1997 Mar 04 (PMID:9050868); Smith LB et al. 2011 Apr 01 (PMID:21071432); D'hondt S et al. 2018 Sep (PMID:29551664);
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 1
Müller GA et al. 2012 Feb (PMID:22038052);
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 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
03/05/2019
EXPERT CURATION (DATE)
Definitive
02/27/2019
EVIDENCE SUMMARY
The relationship between COL3A1 and Ehlers-Danlos syndrome, vascular type (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of February 25th, 2019. Variants in COL3A1 were first reported in humans with this disease as early as 1988 (Superti-Furga et al., PMID 2834369). At least 600 unique variants are found in the Ehlers Danlos Syndrome Variant Database and ~250 more in ClinVar (Byers, 1999; PMID 20301667). This is a well-known gene-disease relationship and there is a significant amount of case-level, segregation and experimental data in the literature, therefore the maximum points for genetic and experimental evidence has been reached. The mechanism for disease is mainly gain-of-function as most cases result from missense variants leading to the substitution of a crucial glycine in the repetitive Gly-X-Y sequence of the triple helix domain, resulting in only 1 in 8 normal mature collagen homotrimers. About 5% of cases are due to haploinsufficiency and are associated with milder phenotypes (Frank et al., 2015; PMID 25758994). This gene-disease relationship is supported by in vitro assays, expression studies, and animal models. In summary, COL3A1 is definitively associated with autosomal dominant Ehlers Danlos Syndrome, vascular type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General GCEP on February 27, 2019 (SOP Version 6).