Gene Validity Curation

GRIA3 - complex neurodevelopmental disorder

Gene: GRIA3 (HGNC:4573)
Classification - 03/23/2020
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: GRIA3 was first reported in relation to X-linked Intellectual Disability in 1999 (Gecz et al., 10644433). At least 10 probands with missense variants have been reported in 8 publications (31406558, 28708303, 25644381, 26637798, 21376300, 24721225, 29016847, 17989220). In addition, loss of function variants in GRIA3 coding region have been reported in 3 probands (1 nonsense, 1 frameshift and 1 intragenic duplication) in 3 publications (PMIDs 31406558, 25644381, 17568425). The proband with 498Kb duplication variant was unable to be formally scored in the GCI since it is >10Kb in size. Though the genetic evidence score shown in the evidence summary is 7.6 points, it should be 8.6 points to account for this duplication variant that could not be scored. Variants in this gene also segregated with disease in at least 2 families (PMID 17989220). This gene-disease association is supported by animal models and expression studies (10644433, 12848940, 18312590,16436610, 22285418). In summary, there is sufficient evidence to support a definitive association of GRIA3 with complex neurodevelopmental disorder. The gene-disease association has been demonstrated in multiple reports and animal model studies, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/06/20 19 (SOP Version 7).
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
Proband with predicted or proven null variant 1.5 0-2 10 2 3 3
Munnich A et al. 2019 Aug 7 (PMID:31406558); Hu H et al. 2016 Jan (PMID:25644381);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 10
2.6
2.6
Wu Y et al. 2007 Nov 13 (PMID:17989220); Philips AK et al. 2014 Apr 11 (PMID:24721225); Munnich A et al. 2019 Aug 7 (PMID:31406558); Hu H et al. 2016 Jan (PMID:25644381); Chérot E et al. 2018 Mar (PMID:28708303); D'Gama AM et al. 2015 Dec 2 (PMID:26637798); Hamdan FF et al. 2011 Mar 11 (PMID:21376300); Davies B et al. 2017 Oct 15 (PMID:29016847);
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 2 2  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 4 2
Wu Y et al. 2007 Nov 13 (PMID:17989220);
Total Summed LOD Score 4    
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) 7.6
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
Gécz J et al. 1999 Dec 15 (PMID:10644433);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 3.5 3.5
Meng Y et al. 2003 Jul 03 (PMID:12848940); Sanchis-Segura C et al. 2006 Jan 25 (PMID:16436610); Adamczyk A et al. 2012 Apr 01 (PMID:22285418);
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 7.6 4 11.6 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
03/23/2020
EXPERT CURATION (DATE)
Definitive
03/23/2020
EVIDENCE SUMMARY
GRIA3 was first reported in relation to X-linked Intellectual Disability in 1999 (Gecz et al., 10644433). At least 10 probands with missense variants have been reported in 8 publications (31406558, 28708303, 25644381, 26637798, 21376300, 24721225, 29016847, 17989220). In addition, loss of function variants in GRIA3 coding region have been reported in 3 probands (1 nonsense, 1 frameshift and 1 intragenic duplication) in 3 publications (PMIDs 31406558, 25644381, 17568425). The proband with 498Kb duplication variant was unable to be formally scored in the GCI since it is >10Kb in size. Though the genetic evidence score shown in the evidence summary is 7.6 points, it should be 8.6 points to account for this duplication variant that could not be scored. Variants in this gene also segregated with disease in at least 2 families (PMID 17989220). This gene-disease association is supported by animal models and expression studies (10644433, 12848940, 18312590,16436610, 22285418). In summary, there is sufficient evidence to support a definitive association of GRIA3 with complex neurodevelopmental disorder. The gene-disease association has been demonstrated in multiple reports and animal model studies, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/06/20 19 (SOP Version 7).