Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ASL : argininosuccinic aciduria

HGNC:746 | MONDO_0008815
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 5
Trevisson E et al. 2007 Jul (PMID:17326097);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
Trevisson E et al. 2007 Jul (PMID:17326097); Walker DC et al. 1990 Dec (PMID:2263616);
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 2
Erez A et al. 2011 Feb 15 (PMID:21312326); Erez A et al. 2011 Nov 13 (PMID:22081021);
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 4 4
Reid Sutton V et al. 2003 Jan (PMID:12559843); Erez A et al. 2011 Nov 13 (PMID:22081021);
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) 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)*
The relationship between ASL and argininosuccinic aciduria (autosomal recessive inheritance) was evaluated using the ClinGen Clinical Validity Framework as of August 28, 2018. Variants in ASL were first reported in humans with this disease as early as 1990 (Walker et al., PMID 2263616) At least 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, splice site, etc) have been reported in humans. Supporting evidence includes case-level data (12 points) and experimental data (6 points). Variants in this gene were curated from 3 publications (Walker et al. 1990, PMID 2263616; Trevisson et al. 2007, PMID 17326097; Trevisson et al, 2009; PMID 19703900). More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the gene product, argininosuccinate lyase, and by the clinical and biochemical features observed in a null and hypomorphic mouse models. In summary, ASL is definitively associated with argininosuccinate lyase deficiency. This classification was approved by the ClinGen Aminoacidopathy Expert Panel on September 5th, 2018.