Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GSTZ1 : maleylacetoacetate isomerase deficiency

HGNC:4643 | MONDO_0060527
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 1
2
4.5
Yang H et al. 2017 Apr (PMID:27876694);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
2.5
Yang H et al. 2017 Apr (PMID:27876694);
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) 4.5
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
0.5
0.5
Fernández-Cañón JM et al. 1998 Jan 2 (PMID:9417084);
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 1.5 1.5
Fernández-Cañón JM et al. 2002 Jul (PMID:12052898);
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) 2

 


 

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 4.5 2 6.5 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
03/26/2019
EXPERT CURATION (DATE)
Moderate
03/22/2019
EVIDENCE SUMMARY
The relationship between GSTZ1 and maleylacetoacetate isomerase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of February, 2019. The GSTZ1 gene is encodes an enzyme that is involved in the phenylalanine/phenylacetate degradation pathway. Most patients with the deficiency show only mild symptoms and remain well without treatment (Yang et al., 2017; PMID 27876694). Variants in GSTZ1 were first reported in humans with this disease in 2017 (Yang et al., 2017; PMID 27876694). At least four variants have been reported in humans (Yang et al., 2017; PMID 27876694). Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays, and a mouse model. 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. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on March 22nd, 2019.