Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DEPDC5 : familial focal epilepsy with variable foci

HGNC:18423 | MONDO_0020310
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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 12 10
Dibbens LM et al. 2013 May (PMID:23542697); Ishida S et al. 2013 May (PMID:23542701); Martin C et al. 2014 Dec (PMID:24283814);
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
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
3
3  
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 Points PMIDs/Notes
Points/Study Max Total 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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
de Calbiac H et al. 2018 May (PMID:29761115);
Functional Alteration Patient cells 1 0 - 2 2
0
Non-patient cells 0.5 0 - 1 0
Swaminathan A et al. 2018 Jun 18 (PMID:29861134); Iffland PH et al. 2018 Jun (PMID:29481864);
Models Non-human model organism 2 0 - 4 4 6 4
Jansen LA et al. 2018 May-Jun (PMID:29950950); de Calbiac H et al. 2018 May (PMID:29761115); Anderson MP et al. 2018 Jun 1 (PMID:29708509);
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 12 4.5 16.5 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
08/24/2018
EXPERT CURATION (DATE)
Definitive
08/24/2018
EVIDENCE SUMMARY
The DEPDC5 gene has been associated with autosomal dominant familial focal epilepsy with variable foci using the ClinGen Clinical Validity Framework as of 8/6/2018. This association was made using case-level data and experimental data. At least 12 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion) have been reported in humans. DEPDC5 was first associated with this disease in humans as early as 2013 (Dibbens et al.). Variants in this gene have been observed in at least 17 probands in 8 publications (PMID: 23542697, 24283814, 23542701, 29761115, 29861134, 29950950, 29708509, 29481864). Variants in this gene segregated with disease in at least 48 additional family members (PMID: 23542697). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (PMID: 23542697). This gene-disease association is supported by animal models, expression studies, and in vitro cell-culture assays (PMID: 29761115, 29861134, 29950950, 29708509, 29481864). Of note, variants in this gene have been found to exhibit reduced penetrance in families with disease (PMID: 23542697, 24283814, 23542701). In summary, DEPDC5 is definitively associated with autosomal dominant familial focal epilepsy with variable foci. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 8/7/2018.