| Gene/Disease Pair: | ASL : argininosuccinic aciduria |
| HGNC:746 | MONDO_0008815 | |
| Mode of Inheritance: | Autosomal recessive inheritance (HP:0000007) |
| Expert Panel: | Aminoacidopathy EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | |||||
| Default | Range | Max | Count | Total | Counted | ||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
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| 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 |
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 | 5 |
10
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12 |
Trevisson E et al. 2007 Jul (PMID:17326097);
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| Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | 6 |
5.25
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Trevisson E et al. 2007 Jul (PMID:17326097); Walker DC et al. 1990 Dec (PMID:2263616);
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| Segregation Evidence | Summed LOD | Family Count | |||||||||
| Candidate gene sequencing | |||||||||||
| Exome/genome or all genes sequenced in linkage region | |||||||||||
| Total Summed LOD Score | |||||||||||
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Case-Control Data
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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 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Count | Total | Counted | ||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 | 2 |
2
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2 |
Erez A et al. 2011 Feb 15 (PMID:21312326); Erez A et al. 2011 Nov 13 (PMID:22081021);
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| Protein Interaction | 0.5 | 0 - 2 | |||||||||
| Expression | 0.5 | 0 - 2 | |||||||||
| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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| 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);
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| Cell culture model | 1 | 0 - 2 | |||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| 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 |
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| 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 | 6 | 18 | YES | ||
| CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
| MODERATE | 7-11 | |||||
| STRONG | 12-18 | |||||
| DEFINITIVE | 12-18 AND replication over time | |||||
| Valid contradictory evidence (Y/N)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
02/07/2019
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| EXPERT CURATION (DATE) |
Definitive
09/15/2018
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| EVIDENCE SUMMARY |
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.
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