Pheochromocytoma: genes and variants

Genes linked to Pheochromocytoma

• SDHB: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial

  It transfers electrons from succinate oxidation through iron-sulfur centers toward ubiquinone in mitochondrial complex II. Heterozygous loss-of-function variants strongly predispose to paraganglioma and pheochromocytoma and can also increase renal-tumor and gastrointestinal-stromal-tumor risk.

  47 disease-causing and 413 uncertain variants in SDHB are linked to Pheochromocytoma.

• SDHD: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial

  It provides a membrane-anchoring component of succinate dehydrogenase and is required for normal complex II electron transfer. Germline loss-of-function variants, often showing a parent-of-origin effect, strongly predispose to head-and-neck paragangliomas and pheochromocytomas.

  14 disease-causing and 221 uncertain variants in SDHD are linked to Pheochromocytoma.

• RET: Proto-oncogene tyrosine-protein kinase receptor Ret

  Its activation by GDNF-family ligands guides development of the enteric nervous system, kidney, and other tissues. Activating variants cause multiple endocrine neoplasia type 2 and can drive cancer, whereas loss-of-function variants are an important cause of Hirschsprung disease.

  5 disease-causing and 182 uncertain variants in RET are linked to Pheochromocytoma.

• VHL: von Hippel-Lindau disease tumor suppressor

  It targets hydroxylated HIF-alpha proteins for ubiquitin-mediated degradation when oxygen is sufficient, keeping hypoxia-response programs suppressed. Loss of function stabilizes HIF signaling and causes von Hippel-Lindau tumor-predisposition syndrome while also driving most clear-cell renal carcinomas.

  4 disease-causing and 20 uncertain variants in VHL are linked to Pheochromocytoma.

• TMEM127: Transmembrane protein 127

  It restrains growth signaling and participates in endomembrane trafficking, including regulation of mTOR-related pathways. Germline loss-of-function variants predispose primarily to pheochromocytoma and paraganglioma and can also occur in selected renal tumors.

  1 disease-causing and 58 uncertain variants in TMEM127 are linked to Pheochromocytoma.

• MAX: Protein max

  It forms DNA-binding dimers with MYC-family proteins and other partners, balancing transcriptional programs that promote or restrain proliferation. Germline loss-of-function variants predispose to pheochromocytoma and paraganglioma, while altered MAX-MYC signaling is central to many cancers.

  0 disease-causing and 24 uncertain variants in MAX are linked to Pheochromocytoma.

Weakly linked (only a few uncertain records): EPAS1.

Where Pheochromocytoma variants cluster

• SDHD Transmembrane (positions 91–111): 7 of 14 disease-causing changes, 3.8× more than its size predicts.
• SDHB 4Fe-4S ferredoxin-type (positions 176–206): 10 of 47 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Pheochromocytoma

Showing 60 of 71.

Uncertain variants in Pheochromocytoma that look disease-causing

Which prediction tools work for Pheochromocytoma

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• EVE: 96 out of 100
• AlphaMissense: 95 out of 100
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100
• MutPred2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 92 out of 100

Same protein, different disease

• Carney-Stratakis syndrome is also caused by SDHB variants; they fall in the same places as the Pheochromocytoma variants (7 disease-causing).
• Mitochondrial complex 2 deficiency, nuclear type 3 is also caused by SDHB variants; they fall in the same places as the Pheochromocytoma variants (7 disease-causing).
• Paragangliomas with sensorineural hearing loss is also caused by SDHD variants; they fall in the same places as the Pheochromocytoma variants (13 disease-causing).
• Carney-Stratakis syndrome is also caused by SDHD variants; they fall in the same places as the Pheochromocytoma variants (11 disease-causing).
• Cowden syndrome is also caused by SDHD variants; they fall in the same places as the Pheochromocytoma variants (11 disease-causing).
• Pheochromocytoma/paraganglioma syndrome 5 is also caused by SDHD variants; they fall in the same places as the Pheochromocytoma variants (4 disease-causing).
• Mitochondrial complex 2 deficiency, nuclear type 3 is also caused by SDHD variants; they fall in the same places as the Pheochromocytoma variants (3 disease-causing).
• Multiple endocrine neoplasia is also caused by RET variants; they fall mostly in different places as the Pheochromocytoma variants (53 disease-causing).
• Hirschsprung disease is also caused by RET variants; they fall mostly in different places as the Pheochromocytoma variants (16 disease-causing).
• Familial medullary thyroid carcinoma is also caused by RET variants; they fall mostly in different places as the Pheochromocytoma variants (13 disease-causing).
• MEN2 phenotype: Unclassified is also caused by RET variants; they fall mostly in different places as the Pheochromocytoma variants (5 disease-causing).
• Von Hippel-Lindau syndrome is also caused by VHL variants; they fall mostly in different places as the Pheochromocytoma variants (147 disease-causing).
• Chuvash polycythemia is also caused by VHL variants; they fall mostly in different places as the Pheochromocytoma variants (116 disease-causing).

Diseases related to Pheochromocytoma

• Hereditary pheochromocytoma and paraganglioma, also linked to MAX, SDHB, SDHD and TMEM127
• Gastrointestinal stromal tumor, also linked to RET and SDHB
• Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHB and SDHD
• Carney-Stratakis syndrome, also linked to SDHB and SDHD
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to SDHB and VHL
• Mitochondrial complex 2 deficiency, nuclear type 3, also linked to SDHB and SDHD
• Renal cell carcinoma, also linked to RET and VHL
• Multiple endocrine neoplasia, also linked to RET
• Von Hippel-Lindau syndrome, also linked to VHL
• Chuvash polycythemia, also linked to VHL
• Cowden syndrome, also linked to SDHD
• Ovarian cancer, also linked to RET

Frequently asked questions

Which genes are linked to Pheochromocytoma?

In CATVariant, Pheochromocytoma is linked to 6 analyzed proteins: SDHB (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial), SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial), RET (Proto-oncogene tyrosine-protein kinase receptor Ret), VHL (von Hippel-Lindau disease tumor suppressor), TMEM127 (Transmembrane protein 127) and MAX (Protein max).

How many genetic variants are linked to Pheochromocytoma?

1,065 variants: 71 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 918 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pheochromocytoma look disease-causing?

19 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SDHB W200C, SDHB Q214H, SDHB H132R, SDHB G69S and SDHB L65F. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Pheochromocytoma?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 22 disease-causing and 79 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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