Inheritance

Autosomal dominant

Prevalence

 1-9 / 1 000 000

Source: ORPHA:29072

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP, accessed 07.11.2023

Clinical Validity Scoring Notes and points

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to Paraganglioma such as head and neck, retroperitoneum [PMID: 21613359], or Renal cell carcinomas (RCCs) [PMID 24334765] and Pheochromocytoma [MIM#171300, PMID: 21156949] with autosomal dominant inheritance. TMEM127 [MIM# 613403] gene encodes the transmembrane protein 127. Heterozygous germline loss of function variants in TMEM127 were first described in 2005 [Dahia PL, et al.; PMID 16266984]. The LOH (loss of heterozygosity) at the TMEM127 locus in tumors examined suggests TMEM127 is a tumor suppressor gene. Genetic evidence from studies on familial and patients with sporadic Pheochromocytomas, as well as RCC are used in this curation [PMID 16266984, 25389632, 20154675 and 28384794].

Experimental evidences such as reduced TMEM127 transcription levels of TMEM127-mutant tumor samples in Pheochromocytomas and Renal cell carcinomas; reduced mTOR signaling, enlarged cells, reduced vesicles and/or increased cell growth compared to non mutant controls in various human cells and murine model cells with reduced or depleted TMEM127 are included for this curation. Evidence that the enlarged cells and increased cell proliferation were rescued by enforced expression of TMEM127 is also included [PMID 20154675, 21156949, 24334765]. In summary, TMEM127 gene is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Source: ClinGen Hereditary Cancer GCEP, accessed 07.11.2023

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer GCEP, accessed 07.11.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 07.11.2023

Molecular Mechanism

Loss of function

Source:

1. 28384794, 20154675

Notes: ClinGen Hereditary cancer GCEP has at least NMD+ variants used for case evidence in their curation:

1. NM_017849.4(TMEM127):c.73A>T (p.Lys25Ter) PMID: 28384794

2. NM_017849.4(TMEM127):c.248del (p.Phe83SerfsTer3) - PMID: 20154675

3. NM_017849.4(TMEM127):c.149dup (p.Pro51AlafsTer57)-PMID: 20154675

Experimental evidence: 50% decrease in mRNA expression in mutant RCC tumors suggests haploinsufficiency, and expression of TMEM127 construct rescued expression. Null mouse embryonic fibroblasts had increased mTOR signaling. (PMID: 24334765).

Penetrance

(list source/PMID)

Reduced (and age-related)

Source: Merged Actionability Release - Clinical Genome Resources

Age of Onset

(list source/PMID)

Adulthood

Source: Merged Actionability Release - Clinical Genome Resources

Severity

Moderate

Clinical Features

Renal cell carcinoma. PCCs primarily, but PGLs have been observed.

PGL-PCC description (from SDHD)

• Multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma and/or a family history.

  • Paragangliomas that arise from neuroendocrine tissue, distributed from the skull base to the pelvic floor.

  • Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. They typically lead to catecholemine excess.

  • Note: Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory.

• Symptoms of PGL/PCC result from effects of catecholamine hypersecretion (sustained or paroxysmal elvations in blood pressure, headach, episodic profuse sweating, forceful palpitations, pallor, and anxiety), palpable abdominal mass, enlarging mass of the skull base/neck, compromise of cranial nerves presenting as hoarseness, dysphagia, soft palate paresis, Horner syndrome; tinnitis.

Sources: PMID: 20301715, Merged Actionability Release - Clinical Genome Resources

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

The TMEM127 gene is associated with autosomal dominant hereditary pheochromocytoma and paraganglioma syndrome, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715). Renal cell carinoma is also observed in individuals with pathogenic variants in TMEM127 (PMID: 24334765).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 07.11.2023 https://broadinstitute.atlassian.net/browse/CIT-130