ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
11567216 Machinis et al (2001): Report of a G>C mutation in the invariant splice-acceptor site resulting in aberrant splicing that was found in individuals in three generations of a family. All family members with the mutation had hypopituitary function, cerebellar defects, and abnormalities of the sella turcica.
18445675 Castinetti (2008): One family with three individuals reported with a frameshift mutation (pedigree A) and functional studies indicating haploinsufficiency. Also provides update on family described by Machinis (PMID: 11567216).
18073311 Pfaeffle (2008): Report includes three families with variable pituitary hormone deficiency and missense changes. Functional studies suggest haploinsufficiency because the protein is inactive for 2/3 mutations.

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.