Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EYA1 : branchio-oto-renal syndrome

HGNC:3519 | MONDO_0007029
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5
Genetic Evidence
Case-Level Data
 Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
 Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
6
6
Stockley TL et al. 2009 Mar (PMID:19206155);
Proband with predicted or proven null variant 1.5 0-2 10 6 6
Orten DJ et al. 2008 Apr (PMID:18220287);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
 Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
2
Li X et al. 2003 Nov 20 (PMID:14628042);
Protein Interaction 0.5 0 - 2 1.5
Li X et al. 2003 Nov 20 (PMID:14628042); Buller C et al. 2001 Nov 15 (PMID:11734542);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.5
Buller C et al. 2001 Nov 15 (PMID:11734542);
Models Non-human model organism 2 0 - 4 4 3 3.5
Johnson KR et al. 1999 Apr (PMID:10072433); Li Y et al. 2010 Feb 17 (PMID:19951260);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
0.5
Li Y et al. 2010 Feb 17 (PMID:19951260);
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
08/30/2018
EXPERT CURATION (DATE)
Definitive
08/30/2018
EVIDENCE SUMMARY
The EYA1 gene has been associated with autosomal dominant Branchio-oto-renal syndrome using the ClinGen Clinical Validity Framework as of 10/17/17. This association was made using case-level data. Multiple missense, nonsense, frameshift and splice-site variants have been reported in humans. EYA1 was first associated with this disease in humans as early as 1997 (Abdelhak et al.​). Nine probands, familial and de novo, were scored for this curation (9020840, 18220287, 19206155). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. This gene-disease association is supported by a spontaneous mouse model, a Xenopus model and a rescue in Xenopus oocytes (10072433, 19951260). In summary, EYA1 is definitively associated with autosomal dominant Branchio-oto-renal syndrome. 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 Hearing Loss Working Group on 11/21/17.