ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
32595695 Hu, et al (2020) identified a de novo nonsense variant (c.1492C>T, p.Arg498Ter) in PPP2R5D via whole exome sequencing in a 6 year old male with a diagnosis of "mental retardation, autosomal dominant 35."
25363768 Iossifov, et al (2014) observed a de novo frameshift variant (c.663delT, p.Glu222Serfs) in PPP2R5D in a female proband with intellectual disability. This same proband is also reported on SFARI as part of the Simons Simplex Collection and is also referenced in several other more recent papers (PMID: 28191890, 31981491).

Haploinsufficiency phenotype comments:

The PPP2R5D gene encodes one of the 15 regulatory B-type subunits of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in humans that is critical for cell signaling and physiology. De novo pathogenic missense variants in the PPP2R5D gene appear to act in a dominant-negative manner to cause PPP2R5D-related neurodevelopmental disorder. This disorder is characterized by mild to severe neurodevelopmental delay, but several other features have also been reported including hypotonia, ataxia, and speech impairment. At the time of this curation at least 13 missense variants have been observed in more than 100 individuals with PPP2R5D-related neurodevelopmental disorder (reviewed in PMID: ?32074998). Functional analysis of PPP2R5D missense variants in human cell lines demonstrated improper formation of the PP2A enzyme and altered phosphorylation patterns (PMID: ?26168268). At this time, isolated deletions of the PPP2R5D gene have not been reported and the only predicted loss of function variants reported in the literature are the two with limited information described above. While there are many cases of missense variation in this gene in individuals with neurodevelopmental disorders, it is unclear at this time whether or not haploinsufficiency is a disease mechanism.

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