Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DCDC2 : nonsyndromic genetic deafness

HGNC:18141 | 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
1
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Grati M et al. 2015 May 1 (PMID:25601850);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 5.09 1
Grati M et al. 2015 May 1 (PMID:25601850);
Total Summed LOD Score 5.09    
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) 4
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 3 1
Grati M et al. 2015 May 1 (PMID:25601850); Ivliev AE et al. 2012 Apr 25 (PMID:22558177);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2 2
Grati M et al. 2015 May 1 (PMID:25601850); Truong DT et al. 2014 Nov (PMID:25130614);
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 4 3 7 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
10/02/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
10/02/2018
REASON(S) FOR CHANGE
Experts approved this curation as Limited, because there is only one family with genetic evidence.
EXPERT CURATION (DATE)
Limited
11/21/2017
EVIDENCE SUMMARY
The DCDC2 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/17/16. This association was made using case-level data only. At least 1 missense variant has been reported in humans. DCDC2 was first associated with this disease in humans as early as 2015 (Grati et al.). Association is seen in at least 1 proband in 1 publications (25601850). Variants in this gene segregated with disease in 7 additional family members. This gene-disease association is supported by a zebrafish model and relevant expression studies. Expert review concluded a limited gene-disease association. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.