Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GSS : inherited glutathione synthetase deficiency

HGNC:4624 | MONDO_0017909
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 2
Shi ZZ et al. 1996 Nov (PMID:8896573); Xia H et al. 2018 Jan 11 (PMID:29340523);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 10
Shi ZZ et al. 1996 Nov (PMID:8896573); Dahl N et al. 1997 Jul (PMID:9215686); Al-Jishi E et al. 1999 Jun (PMID:10450861); Njålsson R et al. 2003 Dec (PMID:14635114); Signolet I et al. 2016 Sep (PMID:27581854); Li X et al. 2015 Nov (PMID:25851806);
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
SNOKE JE et al. 1953 Apr (PMID:13061393); Richman PG et al. 1975 Feb 25 (PMID:1112810);
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 1 0.5
Ingle BL et al. 2018 Nov 29 (PMID:30581542);
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Winkler A et al. 2011 Aug 19 (PMID:21802407);
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) 2.5



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 2.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between GSS and glutathione synthetase deficiency was evaluated using the ClinGen Clinical Validity Framework as of April 20th, 2019. Glutathione is a tripeptide composed of glutamate, cysteine and glycine. It is present in in most mammalian cells and it is involved in several fundamental biological functions, including protection against oxidative damage (PMID 17397529). Glutathione synthetase deficiency is the most common disorder of glutathione metabolism. It is inherited in an autosomal recessive manner. In its most severe form, glutathione synthetase deficiency is characterized by hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system symptoms, and recurrent bacterial infections. However, milder cases, with only mild hemolytic anemia and normal 5-oxoproline levels have also been described (for reviews, see PMIDs 17397529 and 15990954). More than 50 families have been described worldwide (PMID 17397529). Variants in GSS, which encodes glutathione synthetase, were first reported in humans with this condition as early as 1996 (Shi et al, PMID 8896573). Data from 12 patients with 14 unique variants (missense, splicing, nonsense, frameshift, and exon duplication) from 7 publications were curated (Shi et al, 1996, PMID 8896573; Dahl et al, 1997, PMID 9215686; Al-Jishi et al, 1999; PMID 10450861; Li et al, 2015, PMID 25851806; Njålsson et al, 2003; PMID 14635114; Signolet et al, 2016, PMID 27581854; Xia et al, 2018, PMID 29340523). This gene-disease relationship is supported by the biochemical function of glutathione synthetase, resulting in glutathione deficiency and 5-oxoprolinuria in when the enzyme activity is deficient (Snoke et al, 1953; PMID 13061393; Richman et al, 1975, PMID 1112810), as well as functional studies (Ingle et al, 2018; PMID 30581542). In summary, GSS is definitively associated with autosomal recessive glutathione synthetase deficiency. 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 April 26, 2019.