Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ESPN : nonsyndromic genetic deafness

HGNC:13281 | 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 4
5
7
Naz S et al. 2004 Aug (PMID:15286153); Boulouiz R et al. 2008 Dec 01 (PMID:18973245); Naz S et al. 2017 Apr (PMID:27573290);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
2
Wang R et al. 2017 May (PMID:28281779); Sloan-Heggen CM et al. 2015 Dec (PMID:26445815);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 7.5 2
Naz S et al. 2004 Aug (PMID:15286153);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.5    
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) 8.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 2 1
Wang L et al. 2012 Feb 01 (PMID:22048959); Salles FT et al. 2009 Apr (PMID:19287378);
Expression 0.5 0 - 2 3 1.5
Naz S et al. 2004 Aug (PMID:15286153); Zheng L et al. 2000 Aug 04 (PMID:10975527); Rzadzinska A et al. 2005 Nov (PMID:16206170);
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 3.5
Zheng L et al. 2000 Aug 04 (PMID:10975527);
Cell culture model 1 0 - 2 1 0.5
Rzadzinska A et al. 2005 Nov (PMID:16206170);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 1
Taura A et al. 2016 May (PMID:26886463);
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 8.5 5.5 14 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
10/04/2018
EXPERT CURATION (DATE)
Definitive
02/27/2018
EVIDENCE SUMMARY
The ESPN gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 11/29/2017. This association was made using case-level data only. At least 9 nonsense and frameshift variants have been reported in humans. ESPN was first associated with this disease in humans as early as 2004 (Naz et al.). Association is seen in at least 6 probands in 4 publications (15286153, 18973245, 26445815, 28281779). Variants in this gene segregated with disease in 14 additional family members. This gene-disease association is supported by a mouse model, a cell culture rescue model, expression studies and other relevant assays. Of note, missense variants and one in-frame deletion in this gene have been implicated in autosomal dominant nonsyndromic hearing loss. This has been assessed separately. In summary, ESPN is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.