CLCN3

Chr 4ARAD

Cl-/H+ antiporter 3

Also known as: CLC3, ClC-3, NEDHYBA, NEDSBA

NCBI Gene: 1182 ENSG00000109572 UniProt: P51790 OMIM: 600580

The CLCN3 protein functions as an electrogenic H+/Cl- exchanger that mediates chloride-proton exchange across cell membranes and plays a critical role in acidification and neurotransmitter loading of GABAergic synaptic vesicles. Mutations cause neurodevelopmental disorders with seizures, hypotonia, and brain abnormalities, with both autosomal recessive and autosomal dominant inheritance patterns reported. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.22), indicating that even single functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.222 OMIM phenotypes

Clinical Summary— CLCN3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 154 VUS of 203 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 5.37

OE 0.10 (0.05–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.37Z-score

OE missense 0.44 (0.39–0.49)

208 obs / 476.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.22)

0≤0.351.4

Missense OE?0.44 (0.39–0.49)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 4 / 41.2Missense obs/exp: 208 / 476.8Syn Z: 1.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCLCN3-related neurodevelopmental disorder with seizures and brain abnormalitiesLOFAR

strongCLCN3-related neurodevelopmental disorder with hypotonia and brain abnormalitiesOTHERAD

This gene — mechanism propensity

0.5280th %ile

GOF

0.6248th %ile

LOF

0.51top 25%

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

LOFLOEUF 0.22

GOF1 literature citation · 94% of P/LP are missense

DN1 literature citation

Literature Evidence

DNDe novo CLCN3 variants affecting Gly327 cause severe neurodevelopmental syndrome with brain structural abnormalities. These findings were also observed in CLCN3-deficient mice, indicating that the monoallelic missense variant may also have a dominant negative effect.1

GOFDe novo CLCN3 variants affecting Gly327 cause severe neurodevelopmental syndrome with brain structural abnormalities.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 36536096 ↗

ClinVar Variant Classifications

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic13

VUS154

Likely Benign16

Benign2

Conflicting1

Pathogenic

Likely Pathogenic

154

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	0	13	0	0	13
VUS	15	136	3	0	154
Likely Benign	0	5	2	9	16
Benign	0	0	1	1	2
Conflicting	—				1
Total	16	156	6	10	189

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap CLCN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →