Gene Validity Curation

ETV6 - thrombocytopenia 5

Gene: ETV6 (HGNC:3495)
Classification - 01/22/2020
Disease: thrombocytopenia 5 (MONDO_0014536)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: ETV6 was first reported in relation to autosomal dominant thrombocytopenia 5 in 2015 (Zhang et al., 2015; PMID: 25581430). At least 16 unique variants (largely missense, but also nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 20 probands in 7 publications (PMIDs: 25581430, 25807284, 26102509, 27365488, 27663637, 26522332, 29034503). Variants in this gene segregated with disease in 51 additional family members. This gene-disease relationship is supported by the biochemical function of ETV6 as a master hematopoietic transcription factor (PMID: 10514502), it’s functional alteration in both patient (PMID: 27365488, 27663637) and non-patient cells (PMIDs: 25581430, 25807284), as well as a knockdown Zebrafish model (PMID: 25281506) and a conditional knockout mouse model (PMID: 15371326). In summary, ETV6 is definitively associated with autosomal dominant thrombocytopenia 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 4 5 5
Topka S et al. 2015 Jun (PMID:26102509); Moriyama T et al. 2015 Dec (PMID:26522332); Melazzini F et al. 2016 Nov (PMID:27365488); Duployez N et al. 2018 Jan (PMID:29034503);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 12
4.75
4.75
Zhang MY et al. 2015 Feb (PMID:25581430); Noetzli L et al. 2015 May (PMID:25807284); Topka S et al. 2015 Jun (PMID:26102509); Melazzini F et al. 2016 Nov (PMID:27365488); Poggi M et al. 2017 Feb (PMID:27663637);
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 2.3 2.3  
Candidate gene sequencing 4.52 2
Zhang MY et al. 2015 Feb (PMID:25581430); Topka S et al. 2015 Jun (PMID:26102509);
Exome/genome or all genes sequenced in linkage region 4.81 3
Noetzli L et al. 2015 May (PMID:25807284); Melazzini F et al. 2016 Nov (PMID:27365488); Poggi M et al. 2017 Feb (PMID:27663637);
Total Summed LOD Score 9.33    
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
0.5
Lopez RG et al. 1999 Oct 15 (PMID:10514502);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
2
Melazzini F et al. 2016 Nov (PMID:27365488);
Non-patient cells 0.5 0 - 1 3 2
Zhang MY et al. 2015 Feb (PMID:25581430); Noetzli L et al. 2015 May (PMID:25807284);
Models Non-human model organism 2 0 - 4 4 2 3 3
Hock H et al. 2004 Oct 1 (PMID:15371326); Rasighaemi P et al. 2015 Jan (PMID:25281506);
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
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 5.5 17.5 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
02/21/2019
EXPERT CURATION (DATE)
Definitive
01/22/2020
EVIDENCE SUMMARY
ETV6 was first reported in relation to autosomal dominant thrombocytopenia 5 in 2015 (Zhang et al., 2015; PMID: 25581430). At least 16 unique variants (largely missense, but also nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 20 probands in 7 publications (PMIDs: 25581430, 25807284, 26102509, 27365488, 27663637, 26522332, 29034503). Variants in this gene segregated with disease in 51 additional family members. This gene-disease relationship is supported by the biochemical function of ETV6 as a master hematopoietic transcription factor (PMID: 10514502), it’s functional alteration in both patient (PMID: 27365488, 27663637) and non-patient cells (PMIDs: 25581430, 25807284), as well as a knockdown Zebrafish model (PMID: 25281506) and a conditional knockout mouse model (PMID: 15371326). In summary, ETV6 is definitively associated with autosomal dominant thrombocytopenia 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.