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…

Primary Disease Associations & Inheritance

?Neurodevelopmental disorder with seizures and brain abnormalitiesMIM #619517

Neurodevelopmental disorder with hypotonia and brain abnormalitiesMIM #619512

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· G2P