ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23812780 Please note: Most publications regarding the RPS17 gene were based upon the GRCh37 genome assembly. In this assembly, RPS17 was represented as a duplicated gene with 100% sequence identity on chromosome 15 resulting in a total of 4 copies of the gene in a diploid genome. However, in the more recent GRCh38 assembly, this complex region was better characterized and revised to represent only one copy of the gene on chromosome 15. Haploinsufficiency of RPS17 has been demonstrated to result in Diamond Blackfan Anemia (DBA) Landowski et al. 2013 studied 87 unrelated patients with a clinical diagnosis of DBA (thought to be a disorder of ribosome biogenesis and/or function); all patients had previously had negative sequencing studies of the 10 ribosomal protein (RP) genes known at that time. The authors screened the patients using an array with enriched coverage over known RP genes and 117 additional genes "shown to be involved in human ribosomal biogenesis or homologous to yeast pre-ribosomal factors." They identified 6 deletions in RP genes amongst 6 patients, including 2 similar deletions involving exons 3-5 in RPS17. One of these deletions was shown to be de novo; parents were unavailable for testing in the other case. The authors showed that pre-ribosomal RNA processing was affected in cell lines established from patient cells.
20378560 Konno et al. (2010) describe a Japanese male infant with a clinical diagnosis of Diamond-Blackfan anemia and a one-base-pair deletion in exon 2 resulting in a frameshift and premature stop codon.
17647292 Cmejla R et al (2006) identified a patient with known DBA from the Czech DBA registry with a mutation in RPS17. The de novo c.2T>G mutation removes the natural translation initiation start codon. Mutant mRNA was transcribed and the next downstream start codon at position +158 theoretically results in a four amino acid protein. Expression studies showed approximately 50% expression levels, consistent with haploinsufficiency.

Haploinsufficiency phenotype comments:

In the GRCh38 genome assembly submitted in December of 2013, the RPS17 gene was revised to be a single gene copy on each allele. The fact that haploinsufficiency of RPS17 is linked to DBA has not been disputed.

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