GJB3

Chr 1ADARDigenic dominant

gap junction protein beta 3

Also known as: CX31, DFNA2, DFNA2B, EKV, EKVP1

NCBI Gene: 2707 ENSG00000188910 OMIM: 603324

The encoded protein forms connexons that create gap junction channels allowing diffusion of small molecules between adjacent cells. Mutations cause autosomal dominant or digenic hearing loss (sometimes with peripheral neuropathy) and erythrokeratodermia variabilis et progressiva, a progressive skin disorder with variable erythematous and hyperkeratotic patches. The gene shows low constraint to loss-of-function variants, and inheritance patterns include autosomal dominant, autosomal recessive, and digenic mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/AR/Digenic dominantLOEUF 1.323 OMIM phenotypes

Clinical Summary— GJB3

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

1.32LOEUF

pLI 0.002

Z-score 0.96

OE 0.63 (0.33–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.53Z-score

OE missense 1.11 (0.99–1.26)

187 obs / 167.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.33–1.32)

0≤0.351.4

Missense OE?1.11 (0.99–1.26)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 5 / 7.9Missense obs/exp: 187 / 167.8Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGJB3-related erythrokeratodermia variabilis et progressivaOTHERAD

moderateGJB3-related deafness (biallelic)LOFAR

moderateGJB3-related deafness (monoallelic)LOFAD

This gene — mechanism propensity

0.84top 10%

GOF

0.84top 5%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNBased on these findings, we suggest that the CX31V174M mutant may have an effect on the formation and function of the gap junction, and CX31V174M has a trans-dominant negative effect on the function of wild types CX26.1

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

References