Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EDN3 : Waardenburg syndrome type 4B

HGNC:3178 | MONDO_0013201
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 1
1
3
Edery P et al. 1996 Apr (PMID:8630502);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
2
Viñuela A et al. 2009 Oct (PMID:19764030); Kapoor S et al. 2012 July 20 (PMID:22876130);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 3
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Nishio SY et al. 2017 May (PMID:28263850);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Baynash AG et al. 1994 Dec 30 (PMID:8001160); Matera I et al. 2007 Jun (PMID:17516928);
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) 4.5

 


 

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 3 4.5 7.5 NO
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)
Moderate
10/05/2018
EXPERT CURATION (DATE)
Moderate
05/08/2018
EVIDENCE SUMMARY
The EDN3 gene has been associated with autosomal recessive Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 12/8/2017. This association was made using case-level data only. At least 3 variants (missense and frameshift) have been reported in humans. EDN3 was first associated with this disease in humans as early as 1996 (Edery et al.). Association is seen in at least 3 probands in 3 publications (8630502, 19764030, 22876130). Variants in this gene segregated with disease in one additional family member. This gene-disease association is supported by two mouse models with homozygous missense EDN3 variants, which display white spotting, aganglionic megacolon, and early death. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018.