Gene Validity Curation

GLUL - congenital brain dysgenesis due to glutamine synthetase deficiency

Gene: GLUL (HGNC:4341)
Classification - 09/13/2019
Disease: congenital brain dysgenesis due to glutamine synthetase deficiency (MONDO_0012393)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy GCEP
Evidence Summary: GLUL was first reported in relation to autosomal recessive congenital brain dysgenesis due to glutamine synthetase deficiency in 2005 (Häberle J, et al., PMID: 16267323). At least 4 unique variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 16267323, 21353613, 30440076). This gene-disease association is supported by its biochemical function as glutamine synthetase (PMID: 5336023) and several conditional knockout mouse models with partial recapitulation of disease (PMIDs: 25870278, 20140959, 30053506). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
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
2.35
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
2.35
Häberle J et al. 2005 Nov 3 (PMID:16267323); Häberle J et al. 2011 May (PMID:21353613); Ünal Ö et al. 2019 Feb (PMID:30440076);
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) 2.35
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
0.5
0.5
Woolfolk CA et al. 1966 Sep 26 (PMID:5336023);
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
Models Non-human model organism 2 0 - 4 4 3 3 3
Qvartskhava N et al. 2015 Apr 28 (PMID:25870278); He Y et al. 2010 Apr 15 (PMID:20140959); Zhou Y et al. 2019 Feb (PMID:30053506);
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) 3.5

 


 

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 2.35 3.5 5.85 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)
Limited
09/04/2019
EXPERT CURATION (DATE)
Limited
09/13/2019
EVIDENCE SUMMARY
GLUL was first reported in relation to autosomal recessive congenital brain dysgenesis due to glutamine synthetase deficiency in 2005 (Häberle J, et al., PMID: 16267323). At least 4 unique variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 16267323, 21353613, 30440076). This gene-disease association is supported by its biochemical function as glutamine synthetase (PMID: 5336023) and several conditional knockout mouse models with partial recapitulation of disease (PMIDs: 25870278, 20140959, 30053506). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.