Gene Validity Curation

ACVRL1 - telangiectasia, hereditary hemorrhagic, type 2

Gene: ACVRL1 (HGNC:175)
Classification - 08/28/2019
Disease: telangiectasia, hereditary hemorrhagic, type 2 (MONDO_0010880)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between ACVRL1 and hereditary hemorrhagic telangiectasia, type 2 (HHT2), an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 1, 2019. ACVRL1 was first reported in relation to HHT2 in 1996 (Johnson et al., PMID: 8640225). HHT2 is evaluated by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ACVRL1 is a type I TGF-β receptor and interacts with ENG in the TGF-β pathway. ENG is known to cause HHT1. At least 571 ACVRL1 variants, ranging from missense, in-frame indel to nonsense, frameshift, large deletions and whole gene deletions, have been reported in humans (http://www.arup.utah.edu/database/ACVRL1/ACVRL1_welcome.php). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of case level data (12 points): Variants in this gene have been reported in at least 13 probands in 6 publications (PMIDs 86402252, 17384219, 26176610, 9245985 20364125, 20414677). Variants in this gene segregated with disease in 12 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. The mechanism for disease is haploinsufficiency (PMID: 15879500) Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays. A number of mouse and zebra fish models have been developed for HHT (PMID: 17911384, 12588795, 24896812, 12050147). Interaction with ENG in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308). In summary, ACVRL1 is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 2. 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 Hemostasis/Thrombosis Gene Curation Expert Panel on August 28, 2019 (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 1
2
2
Gedge F et al. 2007 Apr (PMID:17384219);
Proband with predicted or proven null variant 1.5 0-2 10 6 9 9
Berg JN et al. 1997 Jul (PMID:9245985); Richards-Yutz J et al. 2010 Jul (PMID:20414677);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
1.45
1.45
Johnson DW et al. 1996 Jun (PMID:8640225); Alaa El Din F et al. 2015 July 15 (PMID:26176610);
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 1.5 1.5  
Candidate gene sequencing 9.04 3
Johnson DW et al. 1996 Jun (PMID:8640225);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 9.04    
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
Guerrero-Esteo M et al. 2002 Aug 9 (PMID:12015308);
Protein Interaction 0.5 0 - 2 1 0.5
Blanco FJ et al. 2005 Aug (PMID:15702480);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4.5 4
Srinivasan S et al. 2003 Mar 1 (PMID:12588795); Park SO et al. 2008 Jan 15 (PMID:17911384); Tual-Chalot S et al. 2014 Jun 4 (PMID:24896812);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4 1
0
Lebrin F et al. 2010 Apr (PMID:20364125);
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 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)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
08/28/2019
EXPERT CURATION (DATE)
Definitive
08/28/2019
EVIDENCE SUMMARY
The relationship between ACVRL1 and hereditary hemorrhagic telangiectasia, type 2 (HHT2), an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 1, 2019. ACVRL1 was first reported in relation to HHT2 in 1996 (Johnson et al., PMID: 8640225). HHT2 is evaluated by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ACVRL1 is a type I TGF-β receptor and interacts with ENG in the TGF-β pathway. ENG is known to cause HHT1. At least 571 ACVRL1 variants, ranging from missense, in-frame indel to nonsense, frameshift, large deletions and whole gene deletions, have been reported in humans (http://www.arup.utah.edu/database/ACVRL1/ACVRL1_welcome.php). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of case level data (12 points): Variants in this gene have been reported in at least 13 probands in 6 publications (PMIDs 86402252, 17384219, 26176610, 9245985 20364125, 20414677). Variants in this gene segregated with disease in 12 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. The mechanism for disease is haploinsufficiency (PMID: 15879500) Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays. A number of mouse and zebra fish models have been developed for HHT (PMID: 17911384, 12588795, 24896812, 12050147). Interaction with ENG in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308). In summary, ACVRL1 is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 2. 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 Hemostasis/Thrombosis Gene Curation Expert Panel on August 28, 2019 (SOP Version 6).