GRXCR1

Chr 4AR

glutaredoxin and cysteine rich domain containing 1

Also known as: DFNB25, PPP1R88

NCBI Gene: 389207ENSG00000215203UniProt: A8MXD5

This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 25MIM #613285
AR
0
Active trials
35
Pathogenic / LP
188
ClinVar variants
1
Pubs (1 yr)
-0.5
Missense Z
1.70
LOEUF
Clinical Summary— GRXCR1
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 93 VUS of 188 total submissions
📖
GeneReview available — GRXCR1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.70LOEUF
pLI 0.000
Z-score -0.43
OE 1.13 (0.75–1.70)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.48Z-score
OE missense 1.11 (0.98–1.26)
174 obs / 157.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.13 (0.75–1.70)
0≤0.351.4
Missense OE1.11 (0.98–1.26)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 15 / 13.3Missense obs/exp: 174 / 157.1Syn Z: -0.49
GOFDN
DN
0.6452th %ile
GOF
0.6540th %ile
LOF
0.4726th %ile

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

GOFprediction above median
DNprediction 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.

ClinVar Variant Classifications

188 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic9
VUS93
Likely Benign48
Benign10
Conflicting2
26
Pathogenic
9
Likely Pathogenic
93
VUS
48
Likely Benign
10
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
22
0
26
Likely Pathogenic
1
2
6
0
9
VUS
2
77
13
1
93
Likely Benign
0
2
22
24
48
Benign
0
3
7
0
10
Conflicting
—2
Total6857025188

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

GRXCR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GRXCR1-related deafness

definitive
ARLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A Novel Exon 2 Deletion Mutation in the GRXCR1 Gene Associated With Non-Syndromic Hearing Loss: A Case Report and Review of Literatures.
Rastad H et al.·Ann Otol Rhinol Laryngol
2023Review
Grxcr1 regulates hair bundle morphogenesis and is required for normal mechanoelectrical transduction in mouse cochlear hair cells.
Lorente-Cánovas B et al.·PLoS One
2022Open AccessFunctional
Murine GRXCR1 Has a Different Function Than GRXCR2 in the Morphogenesis of Stereocilia.
Liu C et al.·Front Cell Neurosci
2021Open Access
Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins.
Blanco-Sánchez B et al.·Cell Rep
2018Open Access
Novel mutation in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness.
Mori K et al.·Ann Otol Rhinol Laryngol
2015
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients