Gene Validity Classification Summary

Gene/Disease Pair:

ARG1 : hyperargininemia

HGNC:663 | MONDO_0008814
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy EP
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 6
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
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
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) 1.5



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 1.5 13.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
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.