GLRX3

Chr 10

glutaredoxin 3

Also known as: GLRX4, GRX3, GRX4, PICOT, TXNL2, TXNL3

NCBI Gene: 10539 ENSG00000108010 UniProt: O76003 OMIM: 612754

This protein functions as a cytosolic iron-sulfur cluster assembly factor that facilitates [2Fe-2S] cluster insertion into cytosolic proteins and is required for hemoglobin maturation. Mutations cause autosomal recessive myopathy with lactic acidosis and sideroblastic anemia, typically presenting in infancy with severe anemia and muscle weakness. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.477), reflecting its essential role in cellular iron-sulfur metabolism.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the glutaredoxin family. Glutaredoxins are oxidoreductase enzymes that reduce a variety of substrates using glutathione as a cofactor. The encoded protein binds to and modulates the function of protein kinase C theta. The encoded protein may also inhibit apoptosis and play a role in cellular growth, and the expression of this gene may be a marker for cancer. Pseudogenes of this gene are located on the short arm of chromosomes 6 and 9. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.48

Clinical Summary— GLRX3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.358

Z-score 3.36

OE 0.23 (0.12–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.15Z-score

OE missense 0.97 (0.85–1.10)

157 obs / 162.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.12–0.48)

0≤0.351.4

Missense OE?0.97 (0.85–1.10)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 5 / 22.0Missense obs/exp: 157 / 162.3Syn Z: 0.73

This gene — mechanism propensity

0.6745th %ile

GOF

0.6443th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.