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Intellectual disability

Gene: KCNK3

Green List (high evidence)
KCNK3 (potassium two pore domain channel subfamily K member 3)
EnsemblGeneIds (GRCh38): ENSG00000171303
EnsemblGeneIds (GRCh37): ENSG00000171303
OMIM: 603220, Gene2Phenotype
KCNK3 is in 6 panels

1 review

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.
Panel Version: 5.286
Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.
Created: 16 Dec 2022, 1:05 p.m. | Last Modified: 16 Dec 2022, 1:05 p.m.
Panel Version: 4.17
Heterozygous variant in the KCNK3 gene already have a well-established link with pulmonary arterial hypertension (OMIM:615344).

However, Sormann et al. 2022 (PMID: 36195757) identified nine unrelated individuals harbouring one of six de novo missense variants in KCNK3 who presented with developmental delay and sleep apnea among other variable features (musculoskeletal and limb anomalies, abnormalities of male genitalia/groin and digestive disturbance). The variants were shown to cause defective X-gating leading to overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways (i.e. GOF), distinct from the PAH mechanism which is caused by LOF variants.
Sources: Literature
Created: 16 Dec 2022, 12:18 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Developmental disorder with sleep apnea

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 16 Dec 2022, 12:18 p.m.

Panel version: 5.286

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • NHS GMS
  • Literature
Phenotypes
  • Developmental disorder with sleep apnea
OMIM
603220
Clinvar variants
Variants in KCNK3
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

11 Oct 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q4_22_promote_green was removed from gene: KCNK3.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to KCNK3. Source Expert Review Green was added to KCNK3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

16 Dec 2022, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: kcnk3 has been classified as Amber List (Moderate Evidence).

16 Dec 2022, Gel status: 1

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

Arina Puzriakova (Genomics England Curator)

gene: KCNK3 was added gene: KCNK3 was added to Intellectual disability. Sources: Literature Q4_22_promote_green tags were added to gene: KCNK3. Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KCNK3 were set to 36195757 Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea Mode of pathogenicity for gene: KCNK3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments