GRXCR2

Chr 5AR

glutaredoxin and cysteine rich domain containing 2

Also known as: DFNB101

NCBI Gene: 643226 ENSG00000204928 UniProt: A6NFK2 OMIM: 615762

The protein contains a glutaredoxin domain that functions in protein S-glutathionylation and is required for maintaining cochlear stereocilia bundles involved in sound detection, specifically ensuring proper localization of TPRN protein in hair cells. Mutations cause autosomal recessive nonsyndromic sensorineural hearing loss (deafness-101). The gene shows tolerance to loss-of-function variants (LOEUF 1.57), consistent with its autosomal recessive inheritance pattern where both copies must be affected to cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing a glutaredoxin domain, which functions in protein S-glutathionylation. A mutation in this gene was found in a family with autoosomal recessive nonsyndromic sensorineural deafness-101. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.571 OMIM phenotype

Clinical Summary— GRXCR2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 56 VUS of 107 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.57LOEUF

pLI 0.000

Z-score 0.13

OE 0.96 (0.60–1.57)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.85Z-score

OE missense 1.20 (1.06–1.37)

167 obs / 138.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.60–1.57)

0≤0.351.4

Missense OE?1.20 (1.06–1.37)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 11 / 11.5Missense obs/exp: 167 / 138.7Syn Z: -0.87

This gene — mechanism propensity

0.6357th %ile

GOF

0.7028th %ile

LOF

0.3939th %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

107 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS56

Likely Benign28

Benign14

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	1	0	5
Likely Pathogenic	3	0	0	0	3
VUS	2	52	1	1	56
Likely Benign	0	2	5	21	28
Benign	0	4	8	2	14
Conflicting	—				1
Total	8	59	15	24	107

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap GRXCR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →