Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EFHC1 : juvenile myoclonic epilepsy

HGNC:16406 | MONDO_0009696
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
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
 
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) 0
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
Suzuki T et al. 2004 Aug (PMID:15258581);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 0.5 0.5
Suzuki T et al. 2009 Mar 15 (PMID:19147686);
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) 1

 


 

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 0 1 1 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)
Limited
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
REASON(S) FOR CHANGE
We have disregarded the very limited functional evidence in light of the complete lack of genetic evidence connecting EFHC1 and JME. In summary, there is convincing evidence disputing the association between EFHC1 and juvenile myoclonic epilepsy (JME). All variants in EFHC1 associated with JME have contradictory evidence for disease association (too common in ExAC/gnomAD, with minor allele frequencies (MAF) of 2.857e-5 to 0.05973). More evidence is needed to either support or refute the role EFHC1 plays in this disease.
EXPERT CURATION (DATE)
Disputed
07/27/2018
EVIDENCE SUMMARY
Numerous probands with juvenile myoclonic epilepsy (JME) and variants in EFHC1 have been reported; however, many of these variants are observed in population databases at frequencies too high to be consistent with JME [PMID: 17634063, 22690745, 22727576, 16839746, 17159113, 15258581]. There were additional variants reported that did not add valuable evidence to the gene disease assertion that may be found in PMID: 18505993.