ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
10590074 Willig et al. in 1999 were the first to describe the relationship between Diamond-Blackfan anemia (DBA) and RPS19 loss of functions variants. They described 11 nonsense variants and 15 indels. They also described several RPS19 missense mutations, splicing defects and intronic variants in individuals with similar phenotypes. Most of those patients had DBA without other clinical manifestations, and they were all considered sporadic cases with confirmed de novo variants. A minority of cases also presented facial malformations, head circumference alterations, intellectual disability, kidney malformation and short stature.
15384984 Gazda et al. in 2004 described several patients with Diamond-Blackfan anemia and loss of function (LoF) variants. Among those patients, 14 different variants were identified, including seven de novo LoF variants. They also demonstrated those variants reduced RPS19 mRNA and protein levels in CD34+ bone marrow cells suggesting haploinsufficiency as a disease mechanism.
15059149 Orfali et al. in 2004 described 104 families from United Kingdom with DBA including 16 (15%) with RPS19 variants, including 4 de novo loss of function variants.
20960466 Boria et al. in 2010 described a DBA Mutation Database consisting in hundreds of variants in 9 different genes including RPS19, which is the most frequently mutated gene in patients with DBA. The DBA Mutation Database registered 129 distinct RPS19 variants carried by 219 patients: 82 of these are de novo and 45 are inherited. The authors themselves reported several additional variants, including 3 nonsense,18 indels and 10 splice-site defects.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.