Gene Validity Curation

AASS - hyperlysinemia (disease)

Gene: AASS (HGNC:17366)
Classification - 06/29/2020
Disease: hyperlysinemia (disease) (MONDO_0009388)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: AASS was first reported in relation to autosomal recessive hyperlysinemia in 2000 (Sacksteder KA, et al., 2000, PMID: 10775527). At least 13 unique variants (e.g. missense, nonsense, frameshift, large deletion, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 23890588, 10775527, 27604308, 23570448). Variants in this gene segregated with disease in 2 additional family members. Of note, this gene has also been implicated in Saccharopinuria. This gene-disease association is supported by its biochemical function in lysine catabolism. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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 4
8
8.85
Sacksteder KA et al. 2000 Jun (PMID:10775527); Tondo M et al. 2013 Nov (PMID:23890588); Houten SM et al. 2013 Apr 9 (PMID:23570448);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
0.85
Reid ES et al. 2016 Nov 1 (PMID:27604308); Houten SM et al. 2013 Apr 9 (PMID:23570448);
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) 8.85
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
Hutzler J et al. 1968 Apr 16 (PMID:4385118);
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 0 0
Dickinson ME et al. 2016 Sep 22 (PMID:27626380);
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

 


 

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 8.85 1 9.85 NO
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)
Moderate
04/24/2020
EXPERT CURATION (DATE)
Moderate
06/29/2020
EVIDENCE SUMMARY
AASS was first reported in relation to autosomal recessive hyperlysinemia in 2000 (Sacksteder KA, et al., 2000, PMID: 10775527). At least 13 unique variants (e.g. missense, nonsense, frameshift, large deletion, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 23890588, 10775527, 27604308, 23570448). Variants in this gene segregated with disease in 2 additional family members. Of note, this gene has also been implicated in Saccharopinuria. This gene-disease association is supported by its biochemical function in lysine catabolism. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.