ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Variation in MTAP has been associated with diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH). From OMIM: "Camacho-Vanegas et al. (2012)(PMID:22464254) describe 2 different heterozygous mutations affecting the previously uncharacterized exon 9 of the MTAP gene in affected members of 5 unrelated families with diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH). Both mutations affected splicing, with altered expression of MTAP isoforms. Serum samples from 2 patients showed accumulation of methylthioadenosine (MTA), whereas MTA was not present in serum from 3 controls. These findings implicated a defect in MTAP enzyme activity in patients with mutations. DNA analysis of tumor tissue from an osteosarcoma of 1 patient showed homozygosity for the mutation with loss of heterozygosity (LOH) of the wildtype allele. The findings of the study suggested that MTAP can also act as a tumor suppressor gene." Given that changes in MTAP have been associated with this phenotype, but the mechanism is not currently understood, we are giving this gene a haploinsufficiency score of 1, to reflect the "emerging" evidence surrounding this gene. Additional information will be necessary to determine whether or not haploinsufficiency truly plays a role in the development of this phenotype.

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