ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: PHEOCHROMOCYTOMA
Evidence for haploinsufficiency phenotype
PubMed ID Description
21156949 Yao et al (2010) sequenced the TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without variants in other susceptibility genes from 8 independent worldwide referral centers. They identified 10 loss of function variants including small deletions, duplications, or nonsense or splice site substitutions that led to truncation or extension of the predicted TMEM127 product. There were reports of families with multiple affected individuals, but familial testing wasn't performed.
20154675 Qin et al (2010) reported 7 unrelated probands with pheochromocytoma; Six of which were truncating variants, consistent with a loss of function. The tumors examined showed loss of heterozygosity at the TMEM127 locus, suggesting a classic mechanism of the 2-hit model of tumor suppressor inactivation. Four of the probands had a family history of pheochromocytoma.
28384794 Bausch et al (2017) used the European-American-Asian Pheochromocytoma-Paraganglioma Registry, a population-based registry of unrelated patients presenting with symptomatic, histopathologically confirmed pheochromocytoma and paraganglioma. They excluded other known susceptibility genes. They found 6 LOF variants. There was evidence of family history and familial testing was performed.
23551308 Elston et al (2018) report a 33-year-old man who presented with an apparently sporadic adrenal pheochromocytoma with a novel TMEM127 germline variant (p.Gln139X). The variant was paternally inherited and the father was asymptomatic at 60 years old.
25389632 Toledo et al (2015) report on 47 individuals (six affected generations) with pheochromocytoma and a c.410-2A>C loss of function TMEM127 variant. The penetrance was calculated to be 3% by age 30 years, 24% by age 50 years and 32% by age 65 years.

Haploinsufficiency phenotype comments:

There are many reports of loss of function variants such as nonsense, framseshift and splice site mutations in the literature associated with familial pheochromocytoma, paraganglioma and renal cell carcinomas (with variable expressivity and reduced penetrance noted). Please note that as there are no reports of whole gene deletions a dominant negative effect can not therefore be completely ruled out.

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