Gene Validity Curation

ARG1 - hyperargininemia

Gene: ARG1 (HGNC:663)
Classification - 06/29/2020
Disease: hyperargininemia (MONDO_0008814)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy
Evidence Summary: ARG1 was first reported in relation to autosomal recessive inheritance of hyperargininemia in 1990 (Haraguchi et al., 1990, PMID: 2365823). At least 43 unique variants (including many missense and nonsense, as well as some in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in the gene have been reported in at least 11 probands in 5 publications (PMIDS: 23859858, 1463019, 1598908, 2365823, 29443755). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ARG1, catalyzing the final step of the urea cycle (PMID: 16747805), and two knockout mouse models which share the biochemical manifestations of hyperammonemia and hyperargininemia while lacking the clinical phenotypes of humans (PMIDs: 12052859, 23920045). In summary, ARG1 is definitively associated with autosomal recessive inheritance of hyperargininemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 6
8.5
12
Haraguchi Y et al. 1990 Jul (PMID:2365823); Grody WW et al. 1992 Jun (PMID:1598908); Uchino T et al. 1992 Dec (PMID:1463019); Wu TF et al. 2013 Aug (PMID:23859858);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
4.5
Uchino T et al. 1992 Dec (PMID:1463019); Wu TF et al. 2013 Aug (PMID:23859858); Cai X et al. 2018 Feb (PMID:29443755);
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
1
1
Bach SJ et al. 1944 (PMID:16747805);
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 2 1 1
Iyer RK et al. 2002 Jul (PMID:12052859); Kasten J et al. 2013 Nov (PMID:23920045);
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

 


 

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 14 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
04/23/2020
EXPERT CURATION (DATE)
Definitive
06/29/2020
EVIDENCE SUMMARY
ARG1 was first reported in relation to autosomal recessive inheritance of hyperargininemia in 1990 (Haraguchi et al., 1990, PMID: 2365823). At least 43 unique variants (including many missense and nonsense, as well as some in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in the gene have been reported in at least 11 probands in 5 publications (PMIDS: 23859858, 1463019, 1598908, 2365823, 29443755). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ARG1, catalyzing the final step of the urea cycle (PMID: 16747805), and two knockout mouse models which share the biochemical manifestations of hyperammonemia and hyperargininemia while lacking the clinical phenotypes of humans (PMIDs: 12052859, 23920045). In summary, ARG1 is definitively associated with autosomal recessive inheritance of hyperargininemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.