Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GNAO1 : early infantile epileptic encephalopathy

HGNC:4389 | MONDO_0016021
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 16
Nakamura K et al. 2013 Sep 5 (PMID:23993195); EuroEPINOMICS-RES Consortium et al. 2014 Oct 2 (PMID:25262651); Talvik I et al. 2015 Apr-Jun (PMID:28503590); Saitsu H et al. 2016 Jan (PMID:25966631); Law CY et al. 2015 Dec 7 (PMID:26485252); Epi4K Consortium et al. 2016 Aug 4 (PMID:27476654); Arya R et al. 2017 Mar 1 (PMID:28202424); Marcé-Grau A et al. 2016 Apr 12 (PMID:27072799); Rim JH et al. 2018 Feb 1 (PMID:29390993); Schorling DC et al. 2017 Oct (PMID:28628939); Danti FR et al. 2017 Apr (PMID:28357411);
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   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 1 0.5
Feng H et al. 2017 Aug 22 (PMID:28747448);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Feng H et al. 2017 Aug 22 (PMID:28747448);
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Valenzuela D et al. 1997 Mar 4 (PMID:9050846);
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) 1.5



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 1.5 13.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
GNAO1 was first reported in relation to autosomal dominant (AD) early infantile epileptic encephalopathy in 2013 [Nakamura et al. PMID: 23993195]. At least 13 unique variants have been reported in humans. These are all missense variants except for one variant that results in a deletion. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 16 probands in 11 publications. The maximum score for genetic evidence (12 pts) has been reached. Experiments performed on non-patient (HEK-293T) cells transfected with human GNAO1 cDNA demonstrated that several variants had reduced expression and loss-of-function in a cAMP inhibition assay. Notably, variant p.Gly203Arg demonstrated gain-of-function effects, but these probands have more prominent movement disorders compared to probands with other variants. The mechanism for disease may be heterozygous loss-of-function [Feng et al. PMID: 28747448], however more experimental evidence is needed to delineate contributions of loss versus gain of function mechanisms. Of note, this gene has also been implicated in autosomal dominant rare genetic movement disorder. This has been assessed separately. In summary, GNAO1 is definitively associated with autosomal dominant early infantile 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 12/18/2018.