Gene Validity Curation

GRIN2A - complex neurodevelopmental disorder

Gene: GRIN2A (HGNC:4585)
Classification - 07/16/2019
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Epilepsy EP
Evidence Summary: The GRIN2A gene has been associated with autosomal dominant complex neurodevelopmental disorder. This disease association was made using case-level data and experimental data. At least 10 variants (missense, frameshift, truncating, deletion, and de novo) were curated from two publications (23933819, 50890276). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by non-patient cells functional alteration and non-human model systems (27839871, 7816096). Additional experimental evidence exists, but was not reviewed in this curation (31158310, 30146685 [additional mouse models], 26312887 [variant expression in cultured neurons]). A treatment paper with N=1 was also reviewed (24839611), but did not qualify as a true genetic rescue; however, it does highlight the potential to translate functional data to targeted treatment. In summary, GRIN2A is definitively associated with autosomal dominant complex neurodevelopmental disorder. 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 7/16/19 (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 1
2
2
Endele S et al. 2010 Nov (PMID:20890276);
Proband with predicted or proven null variant 1.5 0-2 10 7 10.5 10
Endele S et al. 2010 Nov (PMID:20890276); Lemke JR et al. 2013 Sep (PMID:23933819);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.1
0.1
Lemke JR et al. 2013 Sep (PMID:23933819);
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
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1
Cull-Candy S et al. 2001 Jun (PMID:11399431);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Swanger SA et al. 2016 Dec 1 (PMID:27839871);
Models Non-human model organism 2 0 - 4 4 1 1 1
Sakimura K et al. 1995 Jan 12 (PMID:7816096);
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) 2.5

 


 

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 2.5 14.5 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
10/03/2019
EXPERT CURATION (DATE)
Definitive
07/16/2019
EVIDENCE SUMMARY
The GRIN2A gene has been associated with autosomal dominant complex neurodevelopmental disorder. This disease association was made using case-level data and experimental data. At least 10 variants (missense, frameshift, truncating, deletion, and de novo) were curated from two publications (23933819, 50890276). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by non-patient cells functional alteration and non-human model systems (27839871, 7816096). Additional experimental evidence exists, but was not reviewed in this curation (31158310, 30146685 [additional mouse models], 26312887 [variant expression in cultured neurons]). A treatment paper with N=1 was also reviewed (24839611), but did not qualify as a true genetic rescue; however, it does highlight the potential to translate functional data to targeted treatment. In summary, GRIN2A is definitively associated with autosomal dominant complex neurodevelopmental disorder. 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 7/16/19 (SOP Version 6).