Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GRIN1 : complex neurodevelopmental disorder

HGNC:4584 | MONDO_0100038
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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 1
2
2.85
Lemke JR et al. 2016 Jun 7 (PMID:27164704);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
0.85
Lemke JR et al. 2016 Jun 7 (PMID:27164704); Rossi M et al. 2017 Feb (PMID:28051072); Bosch DG et al. 2016 May (PMID:26350515);
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
0
Aggregate Variant Analysis 0-6 1
0
McLaughlin RL et al. 2015 Apr (PMID:25620680);
Total Genetic Evidence Points (Maximum 12) 2.85
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
0
1
Ibrahim F et al. 2013 Feb 21 (PMID:23416048);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Masuho I et al. 2008 Sep (PMID:18729205); Bagasrawala I et al. 2017 Nov 1 (PMID:27664962);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 9 2.5 3.5
Nakao K et al. 2019 Jan 1 (PMID:29394409); Kono M et al. 2019 Feb (PMID:30382582); Single FN et al. 2000 Apr 1 (PMID:10729336); Bygrave AM et al. 2016 Apr 12 (PMID:27070406); Gilman TL et al. 2015 Aug (PMID:25938741); Hirsch SJ et al. 2015 Nov (PMID:25786918); Bygrave AM et al. 2019 Jan 10 (PMID:30687034); Chen PE et al. 2009 Oct (PMID:19794189);
Cell culture model 1 0 - 2 1 1
Straub C et al. 2014 Aug 20 (PMID:25140704);
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) 4.5

 


 

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 2.85 4.5 7.35 NO
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)
Moderate
05/28/2019
EXPERT CURATION (DATE)
Moderate
03/07/2019
EVIDENCE SUMMARY
GRIN1 was first reported in relation to autosmal recessive complex neurodevelopmental disorder in 2016 (Lemke et al., PMID 27164704). At least 3 unique variants (e.g. missense, nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs 27164704, 28051072, 26350515). Variants in this gene segregated with disease in 4 additional family members. The mechanism for disease is traditionally gain of function with autosomal dominant inheritance though some loss of function (LOF) variants have been reported (Lemke 2016 27164704). However, the mechanism for autosomal recessive GRIN1 disorders would presumably be biallelic LOF. Of note, this gene has been assessed separately for autosomal dominant complex neurodevelopmental disorder. This gene-disease association is supported by relevant experimental evidence (e.g. animal models, expression studies, in vitro functional assays, etc.). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Expert Panel on 3/7/2019 (SOP Version 5).