Gene Validity Curation

GABRG2 - epilepsy

Gene: GABRG2 (HGNC:4087)
Classification - 01/21/2020
Disease: epilepsy (MONDO_0005027)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Epilepsy EP
Evidence Summary: GABRG2 was first reported in relation to autosomal dominant epilepsy as early as 2001 (Baulac et al., Wallace et al.; PMID: 11326274, 11326275). Eight unique variants (missense, nonsense, and splice site) are included in this curation to maximize the score for genetic evidence; however, more probands are available in the literature (PMID: 11326274, 12117362, 27066572, 27864268, 28460589, 31004928). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Proband phenotypes included febrile seizures, complex partial seizures, childhood absence epilepsy, GEFS+, epileptic encephalopathy, epilepsy of infancy with migrating focal seizures, Lennox-like epilepsy, and Lennox-Gastaut syndrome. While these phenotypes exist on a spectrum, the Epilepsy GCEP decided to lump these conditions under the general term for epilepsy until more evidence is available. Variants in this gene segregated with disease in 16 additional family members across 3 families (PMID: 11326274, 12117362, 27066572). This gene-disease association is supported by multiple mouse models. In summary, GABRG2 is definitively associated with autosomal dominant epilepsy.
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 4
8
8
Shen D et al. 2017 Jan (PMID:27864268); Zou F et al. 2017 Mar - Jun (PMID:28460589); Komulainen-Ebrahim J et al. 2019 Jul (PMID:31004928);
Proband with predicted or proven null variant 1.5 0-2 10 2 2.5 2.5
Kananura C et al. 2002 Jul (PMID:12117362); Boillot M et al. 2015 Dec (PMID:27066572);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1
1
Baulac S et al. 2001 May (PMID:11326274); Komulainen-Ebrahim J et al. 2019 Jul (PMID:31004928);
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 3.61 1
Baulac S et al. 2001 May (PMID:11326274);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.61    
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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 4 4
Warner TA et al. 2016 Aug 1 (PMID:27340224); Reid CA et al. 2013 Mar 12 (PMID:23408872);
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

 


 

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 16 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
01/21/2020
EXPERT CURATION (DATE)
Definitive
01/21/2020
EVIDENCE SUMMARY
GABRG2 was first reported in relation to autosomal dominant epilepsy as early as 2001 (Baulac et al., Wallace et al.; PMID: 11326274, 11326275). Eight unique variants (missense, nonsense, and splice site) are included in this curation to maximize the score for genetic evidence; however, more probands are available in the literature (PMID: 11326274, 12117362, 27066572, 27864268, 28460589, 31004928). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Proband phenotypes included febrile seizures, complex partial seizures, childhood absence epilepsy, GEFS+, epileptic encephalopathy, epilepsy of infancy with migrating focal seizures, Lennox-like epilepsy, and Lennox-Gastaut syndrome. While these phenotypes exist on a spectrum, the Epilepsy GCEP decided to lump these conditions under the general term for epilepsy until more evidence is available. Variants in this gene segregated with disease in 16 additional family members across 3 families (PMID: 11326274, 12117362, 27066572). This gene-disease association is supported by multiple mouse models. In summary, GABRG2 is definitively associated with autosomal dominant epilepsy.