Gene Validity Curation

ENG - hereditary hemorrhagic telangiectasia

Gene: ENG (HGNC:3349)
Classification - 08/28/2019
Disease: hereditary hemorrhagic telangiectasia (MONDO_0019180)
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 ENG and autosomal dominant Hereditary Hemorrhagic Telangiectasia, Type 1 (HHT1) was evaluated using the ClinGen Clinical Validity Framework as of Apr 11, 2019. ENG was first reported in relation to HHT1 in 1994 (McAllister et al., PMID: 7894484). HHT1 is diagnosed by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ENG is an auxiliary component of the TGF-β receptor system and interacts with ACVRL1 in the TGF-β pathway. ACVRL1 is known to cause HHT2. At least 507 ENG 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/ENG/ENG_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 7894484, 20414677, 30763665, 17384219, 20364125). Variants in this gene segregated with disease in 13 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, 25312062); however a dominant negative mechanism is also reported (PMID: 25312062). Summary of experimental data (6 points): This gene-disease relationship is supported by animal models and in vitro functional assays. A number of mouse models have been developed for HHT (PMID: 10348742, 20224041, 20364125 ). Interaction with ACVRl1 in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308, 25312062). In summary, ENG is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 1. 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
0.5
0.5
Gedge F et al. 2007 Apr (PMID:17384219);
Proband with predicted or proven null variant 1.5 0-2 10 7 10.5 10
McAllister KA et al. 1994 Dec (PMID:7894484); 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 4
2
2
McAllister KA et al. 1994 Dec (PMID:7894484); Gedge F et al. 2007 Apr (PMID:17384219); Ruiz-Llorente L et al. 2019 May 15 (PMID:30763665);
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 1  
Candidate gene sequencing 3.91 2
McAllister KA et al. 1994 Dec (PMID:7894484); Ruiz-Llorente L et al. 2019 May 15 (PMID:30763665);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.91    
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
1
Non-patient cells 0.5 0 - 1 2 1
Mallet C et al. 2015 Feb 15 (PMID:25312062);
Models Non-human model organism 2 0 - 4 4 2 4 4
Li DY et al. 1999 May 28 (PMID:10348742); Mahmoud M et al. 2010 Apr 30 (PMID:20224041);
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 1
0
Lebrin F et al. 2010 Apr (PMID:20364125);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 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 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
08/28/2019
EXPERT CURATION (DATE)
Definitive
08/28/2019
EVIDENCE SUMMARY
The relationship between ENG and autosomal dominant Hereditary Hemorrhagic Telangiectasia, Type 1 (HHT1) was evaluated using the ClinGen Clinical Validity Framework as of Apr 11, 2019. ENG was first reported in relation to HHT1 in 1994 (McAllister et al., PMID: 7894484). HHT1 is diagnosed by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ENG is an auxiliary component of the TGF-β receptor system and interacts with ACVRL1 in the TGF-β pathway. ACVRL1 is known to cause HHT2. At least 507 ENG 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/ENG/ENG_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 7894484, 20414677, 30763665, 17384219, 20364125). Variants in this gene segregated with disease in 13 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, 25312062); however a dominant negative mechanism is also reported (PMID: 25312062). Summary of experimental data (6 points): This gene-disease relationship is supported by animal models and in vitro functional assays. A number of mouse models have been developed for HHT (PMID: 10348742, 20224041, 20364125 ). Interaction with ACVRl1 in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308, 25312062). In summary, ENG is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 1. 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).