ClinGen Dosage Sensitivity Curation Page

RPS6KA3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
8955270 Trivier et al. (1996) analyzed RPS6KA3 (known as RSK2 in this manuscript) for mutations in 76 unrelated patients with Coffin-Lowry Syndrome (CLS). They found 6 mutations: 1 intragenic deletion, 1 nonsense, 2 splice site, and 2 missense. The intragenic deletion was ~2 kb and resulted in a frameshift and stop codon.
9837815 Jacquot et al. (1998) analyzed RPS6KA3 (known as RSK2 in this manuscript) for mutations in 37 patients with CLS. They found 25 mutations: 7 nonsense mutations, 5 frameshift mutations, 8 splice site, and 5 missense.

Haploinsufficiency phenotype comments:

Mutations in RPS6KA3 cause Coffin-Lowry Syndrome (CLS), with severe to profound ID in males, and phenotypes ranging from normal to severe in carrier females.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Madrigal et al. (2007) PMID: 17304053 used MLPA and arrayCGH to identify a 1 Mb duplication including CXorf23, FLJ14503, EIF1AX, and RPS6KA3 genes. The duplication was found in the male proband, 2 affected family members (male cousin and uncle), and the 2 female carriers. The proband did not display feature of CLS, but had nonspecific ID and a "robust build". Tejada et al. (2011) PMID: 21930553 used MLPA and arrayCGH to identify a 1 Mb duplication involving 7 genes (SH3KBP1, BC046187, CXorf23, MAP7D2, EIF1AX, SCARNA9L, and RPS6KA3) in a proband with mild ID. His brother, 2 uncles, mother, and grandmother also carried the duplication. The uncles had learning difficulties and delayed language in childhood; the brother also had LD, but not as severe as the proband. The mother and grandmother did not have LD.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.