Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update

J Clin Endocrinol Metab. 2021 Jan 1;106(1):e350-e364. doi: 10.1210/clinem/dgaa741.


Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL).

Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases.

Main outcome analysis: Clinical, genetic, and functional associations were determined.

Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption.

Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Keywords: TMEM127; genotype-phenotype association; paraganglioma; pheochromocytoma; tumor suppressor gene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / epidemiology
  • Adrenal Gland Neoplasms / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Databases, Genetic
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Pheochromocytoma / epidemiology
  • Pheochromocytoma / genetics*
  • Retrospective Studies
  • Young Adult


  • Membrane Proteins
  • TMEM127 protein, human