Glutathione synthetase deficiency with 5-oxoprolinuria

Summary

Glutathione synthetase deficiency with 5-oxoprolinuria (MONDO:0009947) is a disease caused by GSS (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: GSS (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 303
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glutathione synthetase deficiency with 5-oxoprolinuria
Mondo ID	MONDO:0009947
OMIM	266130
Orphanet	289846
DOID	DOID:0081034
ICD-11	2005562438
SNOMED CT	39112005
UMLS	C0398746
MedGen	97988
GARD	0017330
Is cancer (heuristic)	no

Also known as: glutathione synthetase deficiency · GSSD

Data availability: 303 ClinVar variants · 1 GenCC gene-disease record · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › phagocytic cell dysfunction › defective phagocytic cell engulfment › inherited glutathione synthetase deficiency › glutathione synthetase deficiency with 5-oxoprolinuria

Related subtypes (1): glutathione synthetase deficiency without 5-oxoprolinuria

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

303 retrieved; paginated sample, class counts are floors:

211 likely benign, 23 pathogenic, 22 uncertain significance, 15 likely pathogenic, 14 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2627798	NM_000178.4(GSS):c.[1139_1144del;941C>T]		Pathogenic	no assertion criteria provided
3248260	NC_000020.10:g.(?31368130)(34287210_?)del	ACTL10	Pathogenic	criteria provided, single submitter
1076084	NM_000178.4(GSS):c.922C>T (p.Gln308Ter)	GSS	Pathogenic	criteria provided, single submitter
1163159	NM_000178.4(GSS):c.1139_1144del (p.Val380_Gln381del)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452899	NM_000178.4(GSS):c.706C>T (p.Arg236Ter)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445815	NM_000178.4(GSS):c.656A>C (p.Asp219Ala)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2497893	NM_000178.4(GSS):c.574del (p.Ile192fs)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690620	NM_000178.4(GSS):c.490C>T (p.Arg164Ter)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2702032	NM_000178.4(GSS):c.1045del (p.Gln349fs)	GSS	Pathogenic	criteria provided, single submitter
2714497	NM_000178.4(GSS):c.1103_1104del (p.Glu368fs)	GSS	Pathogenic	criteria provided, single submitter
2716943	NM_000178.4(GSS):c.325C>T (p.Gln109Ter)	GSS	Pathogenic	criteria provided, single submitter
2725232	NM_000178.4(GSS):c.882C>A (p.Cys294Ter)	GSS	Pathogenic	criteria provided, single submitter
2736961	NM_000178.4(GSS):c.1252C>T (p.Arg418Ter)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736963	NM_000178.4(GSS):c.374G>A (p.Arg125His)	GSS	Pathogenic	criteria provided, single submitter
2756529	NM_000178.4(GSS):c.527del (p.Ala176fs)	GSS	Pathogenic	criteria provided, single submitter
2792061	NM_000178.4(GSS):c.587G>A (p.Trp196Ter)	GSS	Pathogenic	criteria provided, single submitter
2793305	NM_000178.4(GSS):c.658C>T (p.Gln220Ter)	GSS	Pathogenic	criteria provided, single submitter
2858234	NM_000178.4(GSS):c.547_550del (p.Asn183fs)	GSS	Pathogenic	criteria provided, single submitter
2874456	NM_000178.4(GSS):c.127G>T (p.Glu43Ter)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2877418	NM_000178.4(GSS):c.49G>T (p.Glu17Ter)	GSS	Pathogenic	criteria provided, single submitter
2903932	NM_000178.4(GSS):c.588G>A (p.Trp196Ter)	GSS	Pathogenic	criteria provided, single submitter
2976093	NM_000178.4(GSS):c.105del (p.Ser36fs)	GSS	Pathogenic	criteria provided, single submitter
3014333	NM_000178.4(GSS):c.1020dup (p.Leu341fs)	GSS	Pathogenic	criteria provided, single submitter
3248261	NC_000020.10:g.(?33516631)(33517413_?)del	GSS	Pathogenic	criteria provided, single submitter
338302	NM_000178.4(GSS):c.4del (p.Ala2fs)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587203	NM_000178.4(GSS):c.1227C>A (p.Cys409Ter)	GSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3637395	NM_000178.4(GSS):c.37C>T (p.Gln13Ter)	GSS	Pathogenic	criteria provided, single submitter
3699755	NM_000178.4(GSS):c.14G>A (p.Trp5Ter)	GSS	Pathogenic	criteria provided, single submitter
4711195	NM_000178.4(GSS):c.146del (p.Pro49fs)	GSS	Pathogenic	criteria provided, single submitter
495702	NM_000178.4(GSS):c.-9+5G>A	GSS	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GSS	Definitive	Autosomal recessive	inherited glutathione synthetase deficiency	3
PRNP	Definitive	Autosomal recessive	inherited glutathione synthetase deficiency	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GSS	Orphanet:289846	Glutathione synthetase deficiency with 5-oxoprolinuria
GSS	Orphanet:289849	Glutathione synthetase deficiency without 5-oxoprolinuria
PRNP	Orphanet:157941	Huntington disease-like 1
PRNP	Orphanet:280397	Familial Alzheimer-like prion disease
PRNP	Orphanet:282166	Inherited Creutzfeldt-Jakob disease
PRNP	Orphanet:356	Gerstmann-Straussler-Scheinker syndrome
PRNP	Orphanet:397606	PrP systemic amyloidosis
PRNP	Orphanet:454745	Kuru
PRNP	Orphanet:466	Fatal familial insomnia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GSS	HGNC:4624	ENSG00000100983	P48637	Glutathione synthetase	gencc,clinvar
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	gencc,clinvar
ACTL10	HGNC:16127	ENSG00000288649	Q5JWF8	Actin-like protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GSS	Glutathione synthetase	Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GSS	Enzyme (other)	yes	6.3.2.3	GSH_synth_subst-bd, Glutathione_synthase, Glutathione_synthase_a-hlx
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom
ACTL10	Other/Unknown	no		Actin, ATPase_NBD

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
frontal pole	1
middle frontal gyrus	1
Brodmann (1909) area 23	1
CA1 field of hippocampus	1
pigmented layer of retina	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GSS	293	ubiquitous	marker	frontal pole, middle frontal gyrus, endometrium epithelium
PRNP	294	ubiquitous	marker	CA1 field of hippocampus, Brodmann (1909) area 23, pigmented layer of retina
ACTL10	119	broad		male germ line stem cell (sensu Vertebrata) in testis, granulocyte, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRNP	2,594
ACTL10	1,848
GSS	996

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRNP	F7VJQ1	70
GSS	P48637	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTL10	Q5JWF8	93.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GSS causes GSS deficiency	1	5710.0×	7e-04	GSS
Glutathione synthesis and recycling	1	475.8×	0.004	GSS
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	237.9×	0.006	PRNP
NCAM1 interactions	1	124.1×	0.008	PRNP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to cadmium ion	2	732.7×	7e-05	GSS, PRNP
response to oxidative stress	2	130.6×	0.001	GSS, PRNP
regulation of glutamate receptor signaling pathway	1	1685.2×	0.005	PRNP
negative regulation of amyloid precursor protein catabolic process	1	1685.2×	0.005	PRNP
negative regulation of dendritic spine maintenance	1	1404.3×	0.005	PRNP
regulation of calcium ion import across plasma membrane	1	1404.3×	0.005	PRNP
positive regulation of glutamate receptor signaling pathway	1	766.0×	0.005	PRNP
dendritic spine maintenance	1	648.1×	0.005	PRNP
negative regulation of long-term synaptic potentiation	1	648.1×	0.005	PRNP
negative regulation of protein processing	1	561.7×	0.005	PRNP
neuron projection maintenance	1	561.7×	0.005	PRNP
negative regulation of interleukin-17 production	1	526.6×	0.005	PRNP
negative regulation of activated T cell proliferation	1	526.6×	0.005	PRNP
response to amyloid-beta	1	495.6×	0.005	PRNP
intracellular copper ion homeostasis	1	468.1×	0.005	PRNP
negative regulation of calcineurin-NFAT signaling cascade	1	468.1×	0.005	PRNP
negative regulation of amyloid-beta formation	1	443.5×	0.005	PRNP
amino acid metabolic process	1	401.2×	0.005	GSS
cellular response to copper ion	1	312.1×	0.006	PRNP
regulation of potassium ion transmembrane transport	1	312.1×	0.006	PRNP
negative regulation of interleukin-2 production	1	290.6×	0.006	PRNP
positive regulation of protein targeting to membrane	1	280.9×	0.006	PRNP
long-term memory	1	210.7×	0.008	PRNP
positive regulation of calcium-mediated signaling	1	210.7×	0.008	PRNP
cellular response to amyloid-beta	1	195.9×	0.008	PRNP
negative regulation of type II interferon production	1	191.5×	0.008	PRNP
negative regulation of T cell receptor signaling pathway	1	183.2×	0.008	PRNP
protein destabilization	1	145.3×	0.009	PRNP
positive regulation of neuron apoptotic process	1	135.9×	0.009	PRNP
positive regulation of protein localization to plasma membrane	1	135.9×	0.009	PRNP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GSS	0	0
PRNP	0	0
ACTL10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GSS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GSS	6.3.2.3	glutathione synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GSS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PRNP, ACTL10

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GSS	1	—
PRNP	0	—
ACTL10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns