Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ASS1 : citrullinemia type I

HGNC:758 | MONDO_0008988
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
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 7
Lee BH et al. 2013 Jan (PMID:23246278); Su TS et al. 1990 Nov 15 (PMID:2246255); Engel K et al. 2009 Mar (PMID:19006241); Diez-Fernandez C et al. 2017 May (PMID:28111830); Kleijer WJ et al. 2006 Mar (PMID:16475226);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
Lee BH et al. 2013 Jan (PMID:23246278);
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
Walser M et al. 1982 Nov (PMID:6763345);
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 1 2 4
Patejunas G et al. 1994 Jan (PMID:8197477);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
Ye X et al. 2000 Oct (PMID:11083500); Lee B et al. 1999 Mar 30 (PMID:10097149);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



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 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Autosomal recessive citrullinemia type I has a long history as a well-known metabolic disorder with the first clinical reports published in the 1960s. Identification and dysfunction of the enzyme product of ASS1, argininosuccinate synthetase, in a citrullinemia patient cell line was first observed in 1967 (PMID 16591537). This same publication asserted that citrullinemia was a genetic inborn error of metabolism, although the ASS1 gene was not mapped until 1977 (PMID 852520) and cloned in 1982 (PMID 6194510). Causative variation in ASS1 was first molecularly confirmed in patient cell-lines (generated at an earlier date) in reports from 1990 (Kobayashi et al. PMID: 2358466, Su et al. PMID: 2246255). At least 130 unique variants (including missense, nonsense, frameshift, splice site, deletions and complex rearrangements) have been reported in humans (PMID: 28111830). Three variants (p.Arg304Trp, c.421-2A>G, and p.Gly390Arg) that are associated with severe disease account for the majority of citrullinemia type I (PMID 12815590). Additionally, at least 8 variants have been associated with mild disease, non-classic presentation of disease, or no clinical symptoms in patients with varying genotypes (PMID 2030163). Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene were curated in 8 cases (PMIDs 28111830, 23246278, 19006241, 16475226, 2246255, 2030163). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the biochemical function of argininosuccinate synthase (Walsner, 1982, PMID 676334). Argininosuccinate synthetase catalyzes the conversion of citrulline and aspartate into argininosuccinate, the third step in the urea cycle. Together with ASL it is responsible for the biosynthesis of arginine in most body tissues. Consistent with this role, deficiency of argininosuccinate synthetase results in accumulation of citrulline and ammonia, leading to hyperammonemic encephalopathy, and deficiency of arginine. The gene-disease relationship is also supported by the biochemical and clinical features observed in murine and bovine animal models (Patejunas et al, 1993, PMID 8197477; (Harper et al, 1999, PMID 2596577) and rescue of these phenotypes in animal models by gene therapy (Lee et al, 1999, PMID 10097149; Ye et al, 2000, PMID 11083500; Chandler et al, 2013, PMID 24131980). More experimental evidence to support the gene-disease relationship is available in the literature but the maximum score for experimental evidence has been reached. In summary, ASS1 is definitively associated with citrullinemia type I (autosomal recessive). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on December 27th, 2018.