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Fetal anomalies

Gene: CLCN3

Green List (high evidence)
CLCN3 (chloride voltage-gated channel 3)
EnsemblGeneIds (GRCh38): ENSG00000109572
EnsemblGeneIds (GRCh37): ENSG00000109572
OMIM: 600580, Gene2Phenotype
CLCN3 is in 4 panels

3 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.
Created: 10 Sep 2026, 9:22 a.m. | Last Modified: 10 Sep 2026, 9:28 a.m.
Panel Version: 8.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517; Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512

Publications

Created: 10 Sep 2026, 9:22 a.m.
Last Modified: 10 Sep 2026, 9:28 a.m.
Panel version: 8.7

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Created: 10 Mar 2026, 12:27 p.m. | Last Modified: 10 Mar 2026, 12:27 p.m.
Panel Version: 6.149
This gene and phenotype were reviewed during meetings between November 2025 & January 2026. The meetings included representatives of the Central & South and North Thames R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Stephanie Allen, Elizabeth Young and Sarah Graham (Central & South GLH), Natalie Chandler and Elizabeth Scotchman (North Thames GLH), and Tazeen Ashraf, Anna De Burca, Natalie Canham, Samantha Doyle, Alice Gardham, Victoria Harrison, Tessa Homfray, Esther Kinning, and Soo-Mi Park (R21 Clinical Oversight Group).
Created: 10 Mar 2026, 11:35 a.m. | Last Modified: 10 Mar 2026, 11:35 a.m.
Panel Version: 6.148
Created: 10 Mar 2026, 11:35 a.m.
Last Modified: 10 Mar 2026, 11:35 a.m.
Panel version: 6.150

Elizabeth Scotchman (North Thames Genomic Laboratory Hub)

Green List (high evidence)

Green on UK panels: epilepsy, intellectual disability and DDG2P. Both monoallelic (missense) and biallelic (LOF) variants cause neurodevelopmental disorders resulting in brain abnormalities. PMID 36536096 describes 2 patients with de novo missense CLCN3 variants affecting the same amino acid (p.(Gly327Ser) and p.(Gly327Asp) - both showed severe neurological phenotypes including global developmental delay, intellectual disability, hypotonia, failure to thrive, and various brain abnormalities which included total agenesis of the corpus callosum. PMID 34186028 describes 2 siblings with homozygous LOF mutation, MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding.
Created: 10 Mar 2026, 11:27 a.m. | Last Modified: 10 Mar 2026, 11:27 a.m.
Panel Version: 6.147

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517; Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512

Publications

Created: 10 Mar 2026, 11:27 a.m.
Last Modified: 10 Mar 2026, 11:27 a.m.
Panel version: 6.147

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512
  • Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Tags
Q3_26_expert_review Q3_26_MOI
OMIM
600580
Clinvar variants
Variants in CLCN3
Penetrance
None
Panels with this gene

History Filter Activity

10 Sep 2026, Gel status: 3

Added Tag, Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q3_26_expert_review tag was added to gene: CLCN3. Tag Q3_26_MOI tag was added to gene: CLCN3.

10 Mar 2026, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Added phenotypes Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517 for gene: CLCN3

9 Mar 2026, Gel status: 3

Created, Added New Source, Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

gene: CLCN3 was added gene: CLCN3 was added to Fetal anomalies. Sources: Expert Review Green Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal