Genes in panel
Regions in panel
Prev Next

Intellectual disability

Gene: CLCN3

Amber List (moderate evidence)

CLCN3 (chloride voltage-gated channel 3)
EnsemblGeneIds (GRCh38): ENSG00000109572
EnsemblGeneIds (GRCh37): ENSG00000109572
OMIM: 600580, Gene2Phenotype
CLCN3 is in 2 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Created: 22 Sep 2021, 12:58 p.m. | Last Modified: 22 Sep 2021, 12:58 p.m.
Panel Version: 3.1299

Zornitza Stark (Australian Genomics)

Green List (high evidence)

11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.

Green for mono-allelic variants, Amber/Red for bi-allelic.
Sources: Literature
Created: 7 Aug 2021, 6:35 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder

Publications

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512
  • Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Tags
Q3_21_rating
OMIM
600580
Clinvar variants
Variants in CLCN3
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

22 Sep 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_21_rating tag was added to gene: CLCN3.

22 Sep 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: clcn3 has been classified as Amber List (Moderate Evidence).

22 Sep 2021, Gel status: 0

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: CLCN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

22 Sep 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517

7 Aug 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Zornitza Stark (Australian Genomics)

gene: CLCN3 was added gene: CLCN3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CLCN3 were set to 34186028 Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CLCN3 was set to Other Review for gene: CLCN3 was set to GREEN gene: CLCN3 was marked as current diagnostic