Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GRIN1 : complex neurodevelopmental disorder

HGNC:4584 | MONDO_0100038
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 7
Hamdan FF et al. 2011 Mar 11 (PMID:21376300); Chen W et al. 2017 Jun (PMID:28228639); Lemke JR et al. 2016 Jun 7 (PMID:27164704);
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
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Lemke JR et al. 2016 Jun 7 (PMID:27164704);
Models Non-human model organism 2 0 - 4 4
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) 0.5



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 0.5 12.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between GRIN1 and autosomal dominant (AD) complex neurodevelopmental disorder was evaluated using the ClinGen Clinical Validity Framework as of 11/19/2018. Variants in GRIN1 were first reported in humans with this disease as early as 2011 (Hamdan et al., PMID: 21376300). At least 16 variants (e.g. missense, in-frame indel, in-frame duplications) have been reported in humans (PMID: 21376300, 27164704, 25864721, 28228639). Evidence supporting this gene-disease relationship includes de novo case-level data, and experimental data. Of note, there are animal models supporting that loss of function of the GRIN1 protein results in complex neurodevelopmental disorder, but these models are full knockouts that are used to support the gene's association with autosomal recessive disease. Variants in this gene have been reported in at least 33 probands in 4 publications (PMID: 21376300, 27164704, 25864721, 28228639). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is predicted to be dominant negative/haploinsufficiency (PMID: 27164704). Of note, this gene has also been implicated in causing disease in an autosomal recessive pattern. This will be assessed separately. This gene-disease association is supported by in vitro functional assays showing that the de novo variants may cause a dominant negative impact resulting in a loss of function of the transmembrane domain (PMID: 27164704). In summary, GRIN1 is definitively associated with AD complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.