Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ESRRB : nonsyndromic genetic deafness

HGNC:3473 | MONDO_0019497
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 2
4
6.5
Collin RW et al. 2008 Jan (PMID:18179891); Lee K et al. 2011 Sep 25 (PMID:22567352);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 7
2.5
Collin RW et al. 2008 Jan (PMID:18179891); Ben Saïd M et al. 2011 Nov-Dec (PMID:21802533); Šafka Brožková D et al. 2012 Nov (PMID:22951369); Ji H et al. 2014 Sep 10 (PMID:25342930);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.45 1
Collin RW et al. 2008 Jan (PMID:18179891);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.45    
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) 8
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Collin RW et al. 2008 Jan (PMID:18179891);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Chen J et al. 2007 Sep (PMID:17765677);
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) 3

 


 

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 8 3 11 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)
Moderate
11/27/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Definitive
11/27/2018
REASON(S) FOR CHANGE
An additional 2 unpublished internal Partners LMM cases brings the final classification to Definitive.
EXPERT CURATION (DATE)
Definitive
04/24/2018
EVIDENCE SUMMARY
The relationship between ESRRB and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/1/2017. Variants in ESRRB were first associated with this disease in humans as early as 2008 (Collin et al.). At least 9 variants (missense, in-frame del, frameshift, and a multiexon deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 9 probands in 4 publications as well as unpublished data (18179891, 21802533, 22567352, 22951369, Partners LMM unpublished data). Variants in this gene segregated with disease in 7 additional family members. This gene-disease association is supported by a mouse model and relevant expression studies (Chen et al. 2007, Collin et al. 2008). In summary, ESRRB is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 4/24/2018​.