Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GABRA1 : developmental and epileptic encephalopathy

HGNC:4075 | MONDO_0100062
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
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 22
42
12
Johannesen K et al. 2016 Sep 13 (PMID:27521439); Epi4K Consortium et al. 2013 Sep 12 (PMID:23934111); Kodera H et al. 2016 Apr (PMID:26918889); Carvill GL et al. 2014 Apr 8 (PMID:24623842); Farnaes L et al. 2017 Sep (PMID:28864462);
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 2
1
1
Johannesen K et al. 2016 Sep 13 (PMID:27521439); Carvill GL et al. 2014 Apr 8 (PMID:24623842);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
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
GTEx Consortium et al. 2015 May 08 (PMID:25954001);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Johannesen K et al. 2016 Sep 13 (PMID:27521439);
Models Non-human model organism 2 0 - 4 4
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 12 1 13 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
05/24/2019
EXPERT CURATION (DATE)
Definitive
05/21/2019
EVIDENCE SUMMARY
GABRA1 was first reported in relation to autosomal dominant (AD) developmental and epileptic encephalopathy in 2014 [Epi4K Consortium et al. PMID: 23934111]. At least 14 unique variants have been reported in humans. These are all missense variants and most of de novo inheritance. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 23 probands in 5 publications. The maximum score for genetic evidence (12 pts) has been reached. The patch clamp analysis Experiments performed on Xenopus oocytes co-expressed with human GABRA1 cDNA demonstrated that several variants had significantly reduced current amplitudes and loss-of-function in sensitivity to GABA [Johannesen et al. PMID: 27521439, Carvill et al. PMID: 24623842]. Also, this gene is exclusively expressed in human brain tissue [GTEx Consortium et al. PMID: 25954001]. The mechanism for disease may be heterozygous loss-of-function [Johannesen et al. PMID: 27521439]. Of note, this gene has also been implicated in idiopathic/genetic generalized epilepsies. This has been assessed separately. In summary, GABRA1 is definitively associated with autosomal dominant developmental and epileptic encephalopathy. 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 Epilepsy GCEP on 05/21/2019.