GSS

glutathione synthetase

Basic information

Region (hg38): 20:34928431-34956027

Links

ENSG00000100983 ∙ NCBI:2937 ∙ OMIM:601002 ∙ HGNC:4624 ∙ Uniprot:P48637 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• glutathione synthetase deficiency with 5-oxoprolinuria (Strong), mode of inheritance: AR
• inherited glutathione synthetase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Glutathione synthetase deficiency	AR	Biochemical;Hematologic; Pharmacogenomic	Medical therapy (eg, N-acetylcysteine, vitamin E), may improve outcomes, especially if administered early; Hemolysis-causing drugs should be avoided; Acidosis can be medically corrected	Biochemical; Hematologic; Neurologic; Ophthalmologic	13731008; 5901982; 5486400; 5476481; 481537; 3944259; 2502672; 1770788; 1986110; 7937585; 8896573; 11445798; 15717202; 15990954; 16435214; 17206463; 17479648; 19728142; 21988557

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GSS gene.

• Gluthathione synthetase deficiency (185 variants)
• not provided (80 variants)
• Inborn genetic diseases (34 variants)
• not specified (21 variants)
• Glutathione synthetase deficiency without 5-oxoprolinuria (2 variants)
• Glutathione synthetase deficiency with 5-oxoprolinuria (1 variants)
• GSS-related condition (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GSS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	51		52
missense	4	4	80			88
nonsense	5	2				7
start loss		1				1
frameshift	3	5	3			11
inframe indel		1	1			2
splice donor/acceptor (+/-2bp)		3				3
splice region	1		3	11		15
non coding			13	27	15	55
Total	12	16	98	78	15

Highest pathogenic variant AF is 0.0000394

Variants in GSS

This is a list of pathogenic ClinVar variants found in the GSS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-34928437-T-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 13, 2018)
20-34928438-C-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 13, 2018)
20-34928505-C-T		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 12, 2018)
20-34928643-G-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 12, 2018)
20-34928645-G-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 13, 2018)
20-34928647-G-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 12, 2018)
20-34928738-T-C		Inherited glutathione synthetase deficiency	Benign/Likely benign (Dec 01, 2021)
20-34928759-C-A		Inherited glutathione synthetase deficiency	Likely benign (Jan 13, 2018)
20-34928760-C-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 13, 2018)
20-34928797-G-A		Inherited glutathione synthetase deficiency	Uncertain significance (Jan 13, 2018)
20-34928808-C-G		Inherited glutathione synthetase deficiency	Conflicting classifications of pathogenicity (Jan 13, 2018)
20-34928826-C-T		Inherited glutathione synthetase deficiency	Benign (Jan 12, 2018)
20-34928831-C-A		Inherited glutathione synthetase deficiency	Likely benign (Mar 26, 2020)
20-34928846-G-T		not specified	Uncertain significance (Jul 19, 2023)
20-34928864-C-T		Inherited glutathione synthetase deficiency	Likely benign (Jan 13, 2024)
20-34928865-G-A			Uncertain significance (Jun 04, 2015)
20-34928879-A-G		Inherited glutathione synthetase deficiency	Likely benign (Jun 09, 2023)
20-34928880-T-C			Uncertain significance (Mar 10, 2023)
20-34928891-G-A		not specified • Inherited glutathione synthetase deficiency • Inborn genetic diseases	Likely benign (Nov 01, 2023)
20-34928900-G-C		Inherited glutathione synthetase deficiency	Likely benign (May 20, 2023)
20-34928909-T-A		Inherited glutathione synthetase deficiency	Likely benign (Oct 13, 2023)
20-34928913-T-C			Uncertain significance (Oct 11, 2021)
20-34928920-C-T		Inherited glutathione synthetase deficiency	Uncertain significance (Jul 27, 2022)
20-34928921-G-A		Inborn genetic diseases • Inherited glutathione synthetase deficiency	Likely benign (Dec 03, 2023)
20-34928924-C-T		Inherited glutathione synthetase deficiency	Likely benign (Jul 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GSS	protein_coding	protein_coding	ENST00000216951	12	27385

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000176	0.993	125641	0	107	125748	0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.774	227	262	0.865	0.0000160	3049
Missense in Polyphen		88	100.51	0.87551		1197
Synonymous	1.11	93	108	0.864	0.00000625	988
Loss of Function	2.43	14	27.9	0.502	0.00000176	282

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000326	0.000326
Ashkenazi Jewish	0.00447	0.00447
East Asian	0.000490	0.000489
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000290	0.000290
Middle Eastern	0.000490	0.000489
South Asian	0.000163	0.000163
Other	0.000815	0.000815

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Glutathione synthetase deficiency (GSS deficiency) [MIM:266130]: Severe form characterized by an increased rate of hemolysis and defective function of the central nervous system. {ECO:0000269|PubMed:27581854, ECO:0000269|PubMed:8896573, ECO:0000269|PubMed:9215686}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glutathione synthetase deficiency of erythrocytes (GLUSYNDE) [MIM:231900]: Mild form causing hemolytic anemia. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Glutathione metabolism - Homo sapiens (human);Cysteine and methionine metabolism - Homo sapiens (human);Ferroptosis - Homo sapiens (human);2-Hydroxyglutric Aciduria (D And L Form);Gamma-glutamyl-transpeptidase deficiency;5-oxoprolinase deficiency;Gamma-Glutamyltransferase Deficiency;Glutathione Metabolism;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Glutathione Synthetase Deficiency;Succinic semialdehyde dehydrogenase deficiency;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;5-Oxoprolinuria;Glutamate Metabolism;Glutathione metabolism;Trans-sulfuration and one carbon metabolism;Amino Acid metabolism;One carbon metabolism and related pathways;Metapathway biotransformation Phase I and II;Glutathione conjugation;Phase II - Conjugation of compounds;Glutamate Glutamine metabolism;Biological oxidations;Metabolism;glutathione biosynthesis;γ-glutamyl cycle;Glutathione synthesis and recycling (Consensus)

Recessive Scores

• pRec: 0.328

Intolerance Scores

• loftool: 0.256
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.73

Haploinsufficiency Scores

• pHI: 0.266
• hipred: N
• hipred_score: 0.443
• ghis: 0.543

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.665

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gss
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: cellular amino acid metabolic process;glutathione biosynthetic process;response to oxidative stress;nervous system development;aging;response to xenobiotic stimulus;response to nutrient levels;response to tumor necrosis factor;response to amino acid;response to cadmium ion
• Cellular component: cytosol;extracellular exosome
• Molecular function: magnesium ion binding;glutathione synthase activity;protein binding;ATP binding;glycine binding;identical protein binding;protein homodimerization activity;glutathione binding