Gene Validity Classification Summary

Gene/Disease Pair:

EPS8 : nonsyndromic sensorineural deafness

MONDO:0014428 | ORPHA:90636 | OMIM:615974
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
0
Proband with predicted or proven null variant 1.5 0-2 10 0.00 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.50
0.5
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
4.00
Behlouli A et al. 2014 Apr 17 (PMID:24741995); Yan D et al. 2016 Aug (PMID:27344577);
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
0.00
0  
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 Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 4.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
2
Protein Interaction 0.5 0 - 2 1.00
Manor U et al. 2011 Jan 25 (PMID:21236676); Ebrahim S et al. 2016 May 3 (PMID:27117407);
Expression 0.5 0 - 2 1.50
Manor U et al. 2011 Jan 25 (PMID:21236676); Zampini V et al. 2011 Apr (PMID:21526224); Behlouli A et al. 2014 Apr 17 (PMID:24741995);
Functional Alteration Patient cells 1 0 - 2 2
0.00
0.5
Non-patient cells 0.5 0 - 1 0.50
Zampini V et al. 2011 Apr (PMID:21526224);
Models Non-human model organism 2 0 - 4 4 2.50 2.5
Manor U et al. 2011 Jan 25 (PMID:21236676); Zampini V et al. 2011 Apr (PMID:21526224); Tavazzani E et al. 2016 Jul 22 (PMID:27132230);
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
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 4.5 5 9.5 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
10/27/2016
EXPERT CURATION (DATE)
MODERATE
04/26/2017
The EPS8 gene has been associated with ARNSHL in (at least) 3 probands in 2 publications. 3 unique variants (missense, nonsense, frameshift) have been reported in humans, and variants in this gene segregated with disease in 2 additional family members. EPS8 was first associated with this disease in humans in 2014 (Behlouli et al.). The mechanism for disease based on current case data may be biallelic loss of function, but more cases will be needed to establish this. This gene-disease association is supported by the gene's expression within the stereocilia of the inner ear, a knockout mouse model demonstrating hearing loss and functional alteration of biophysical properties of membrane potentials, and its interaction with WHRN, a known hearing loss gene (Zampini 2011, Furness 2013, Behlouli 2014, Ebraham 2016). 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 4/26/2017.