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Intellectual disability

Gene: RPS6KC1

Amber List (moderate evidence)
RPS6KC1 (ribosomal protein S6 kinase C1)
EnsemblGeneIds (GRCh38): ENSG00000136643
EnsemblGeneIds (GRCh37): ENSG00000136643
OMIM: 617517, Gene2Phenotype
RPS6KC1 is in 4 panels

1 review

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Created: 5 Jan 2026, 10:48 a.m. | Last Modified: 5 Jan 2026, 10:48 a.m.
Panel Version: 9.217
PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Created: 5 Jan 2026, 10:30 a.m. | Last Modified: 5 Jan 2026, 5:42 p.m.
Panel Version: 9.217

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

Created: 5 Jan 2026, 10:30 a.m.
Last Modified: 5 Jan 2026, 5:42 p.m.
Panel version: 9.216

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • neurodevelopmental disorder, MONDO:0700092
Tags
Q1_26_promote_green
OMIM
617517
Clinvar variants
Variants in RPS6KC1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

5 Jan 2026, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).

5 Jan 2026, Gel status: 1

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q1_26_promote_green tag was added to gene: RPS6KC1.

5 Jan 2026, Gel status: 1

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

Achchuthan Shanmugasundram (Genomics England Curator)

gene: RPS6KC1 was added gene: RPS6KC1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPS6KC1 were set to 41130203 Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: RPS6KC1 was set to GREEN