Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GABRB3 : developmental and epileptic encephalopathy

HGNC:4083 | 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 11
Epi4K Consortium et al. 2016 Aug 4 (PMID:27476654); Zhang Y et al. 2015 Nov 6 (PMID:26544041); Bagnall RD et al. 2016 Apr (PMID:26704558); Le SV et al. 2017 Aug (PMID:28544625); Štěrbová K et al. 2018 Jun (PMID:29444535); Papandreou A et al. 2016 Apr (PMID:26645412);
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
Epi4K Consortium et al. 2016 Aug 4 (PMID:27476654);
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
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 3 3
Møller RS et al. 2017 Jan 31 (PMID:28053010); Hernandez CC et al. 2017 Nov 21 (PMID:29162865); Janve VS et al. 2016 May (PMID:26950270);
Models Non-human model organism 2 0 - 4 4 2 2 2
DeLorey TM et al. 2008 Mar 5 (PMID:17983671); Ferguson C et al. 2007 Oct 10 (PMID:17927825);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
GABRB3 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2016 (Epi4K Consortium et al., 27476654). Evidence supporting this gene-disease relationship includes case-level and experimental data. Many de novo missense variants have been reported in humans, which reaches the maximum score for genetic evidence (Epi4K Consortium et al. 2016, 27476654; Zhang et al. 2015, 26544041; Le et al. 2017, 28544625; Sterbova et al. 2018, 29444535). This gene-disease association is supported by functional alteration evidence and mouse models (Janve et al. 2016, 26950270; Hernandez et al. 2017, 29162865; Moller et al. 2017, 28053010; DeLorey et al. 2008, 17983671; Ferguson et al. 2007; 17927825). A global knockout and a forebrain selective knockout mouse model were each scored for replicating seizure phenotypes, but were downgraded because the homozygous models do not replicate the heterozygous mechanism observed in humans. Of note, missense variants have been reported to segregate in three families with familial GEFS+. One affected individual of each family is likely a phenocopy, as they do not carry the reported GABRB3 variant (Moller et al. 2017, 28053010). These families were not curated as part of the GABRB3-autosomal dominant developmental epileptic encephalopathy. In summary, GABRB3 is definitively associated with autosomal dominant developmental 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 ClinGen Epilepsy Gene Curation Expert Panel on 2/5/2019.