Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DIAPH3 : auditory neuropathy

HGNC:15480 | MONDO_0021944
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 1
1
1
Schoen CJ et al. 2010 Jul 27 (PMID:20624953);
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   Summed LOD Family Count 1 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.7 1
Schoen CJ et al. 2010 Jul 27 (PMID:20624953);
Total Summed LOD Score 2.7    
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) 2
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
Schoen CJ et al. 2013 Feb 18 (PMID:23441200);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Schoen CJ et al. 2010 Jul 27 (PMID:20624953);
Non-patient cells 0.5 0 - 1 1 0.5
Schoen CJ et al. 2010 Jul 27 (PMID:20624953);
Models Non-human model organism 2 0 - 4 4 2 2.5 2.5
Schoen CJ et al. 2010 Jul 27 (PMID:20624953); Schoen CJ et al. 2013 Feb 18 (PMID:23441200);
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 2 4.5 6.5 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
10/01/2018
EXPERT CURATION (DATE)
Moderate
03/29/2017
EVIDENCE SUMMARY
The DIAPH3 gene has been associated with autosomal dominant auditory neuropathy using the ClinGen Clinical Validity Framework as of 12/13/16. This association was made with one family segregating with a regulatory c.-172G>A variant (Schoen et al. 2010). Both heterozygous and homozygous affected individuals were identified in the consanguineous family, with homozygous individuals having an earlier onset of auditory neuropathy. This gene-disease association is supported by two transgenic mouse lines and relevant expression and functional alteration studies (20624953, 23441200). 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 3/29/17.