GSR

protein-coding

glutathione-disulfide reductase

Gene summary

This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. This enzyme is a homodimeric flavoprotein. It is a central enzyme of cellular antioxidant defense, and reduces oxidized glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant. Rare mutations in this gene result in hereditary glutathione reductase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, Aug 2010]

MANE transcript

NM_000637.5

Inheritance

ClinVar variants

P:10U:126B:46

Top phenotype

Anemia, congenital, nonspherocytic hemolytic, 10

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr8:30,678,066-30,727,846

External References & Databases

Ensembl (ENSG00000104687)

Transcript & Mutation Effects

hg38 • Region Span ~49.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemolytic anemia due to glutathione reductase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019531

Submitter: Orphanet

hemolytic anemia due to glutathione reductase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019531

Submitter: Labcorp Genetics (formerly Invitae)

hemolytic anemia due to glutathione reductase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019531

Submitter: PanelApp Australia

hemolytic anemia due to glutathione reductase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019531

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Anemia, congenital, nonspherocytic hemolytic, 10AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals are susceptible to hemolytic anemia, and awareness may allow early management as well as avoidance of triggers of hemolysis (eg, fava beans)

Refs: 6017801; 17185460

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GSR variants in ClinVar

4 Conditions Cataloged

not providedTotal: 95

Hemolytic anemia due to glutathione reductase deficiencyTotal: 89

not specifiedTotal: 86

GSR-related disorderTotal: 21

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000637.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	29 clinvar	2 clinvar	33
missense	1 clinvar	1 clinvar	121 clinvar	13 clinvar	2 clinvar	138
nonsense	1 clinvar	2 clinvar	1 clinvar			4
start loss						0
frameshift		3 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)	2 clinvar		1 clinvar			3
Total	4	6	126	42	4	182

Highest pathogenic variant AF is 0.00009516082

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000637.5	RefSeq	NP_000628.2	13	MANE Select
ENST00000221130.11	Ensembl	ENSP00000221130.5	13	MANE Select
NM_001195102.3	RefSeq	NP_001182031.1	12	Standard
NM_001195103.3	RefSeq	NP_001182032.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone synthesis - Homo sapiens (human)
Glutathione metabolism - Homo sapiens (human)
Oxidative Stress Pathway (Erythrocyte)
Pathway_PA165980337
Oxidative Stress Pathway (Erythrocyte)

Biological Process

glutathione metabolic process
nucleobase-containing small molecule interconversion
electron transport chain
cellular response to oxidative stress
cell redox homeostasis

Molecular Function

glutathione-disulfide reductase activity
electron transfer activity
flavin adenine dinucleotide binding
NADP binding

Cellular Component

mitochondrion
mitochondrial matrix
cytosol
external side of plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000221130
Coding exons: 13
Length: 49861
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.512	247	271	0.912	0.0000154	3360
Missense (PolyPhen)		115	127.17	0.90428		1477
Synonymous	0.585	95	103	0.927	0.00000640	1047
Loss of Function	1.89	13	22.7	0.572	0.00000114	290

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00029	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Maintains high levels of reduced glutathione in the cytosol.;

Intolerance Scores

LoFtool: 0.468
RVIS EVS: -0.36
RVIS percentile EVS: 29.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.909

Gene Damage Prediction

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