Pheochromocytoma/paraganglioma syndrome 5: genes and variants

Genes linked to Pheochromocytoma/paraganglioma syndrome 5

• 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.

  48 disease-causing and 428 uncertain variants in SDHB are linked to Pheochromocytoma/paraganglioma syndrome 5.

• SDHC: Succinate dehydrogenase cytochrome b560 subunit, mitochondrial

  It anchors succinate dehydrogenase to the inner mitochondrial membrane and helps transfer electrons from the catalytic subunits to ubiquinone. Heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and some gastrointestinal stromal tumors.

  16 disease-causing and 256 uncertain variants in SDHC are linked to Pheochromocytoma/paraganglioma syndrome 5.

• SDHA: Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial

  It catalyzes oxidation of succinate to fumarate while transferring electrons into respiratory-chain complex II, directly linking the TCA cycle with oxidative phosphorylation. Biallelic deficiency can cause mitochondrial disease, while heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and selected gastrointestinal stromal tumors.

  14 disease-causing and 1,084 uncertain variants in SDHA are linked to Pheochromocytoma/paraganglioma syndrome 5.

• 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.

  4 disease-causing and 4 uncertain variants in SDHD are linked to Pheochromocytoma/paraganglioma syndrome 5.

• SDHAF2: Succinate dehydrogenase assembly factor 2, mitochondrial

  It is required for covalent flavin attachment and maturation of the SDHA catalytic subunit, enabling normal succinate dehydrogenase activity. Germline loss-of-function variants can predispose to hereditary head-and-neck paragangliomas through functional loss of complex II.

  0 disease-causing and 30 uncertain variants in SDHAF2 are linked to Pheochromocytoma/paraganglioma syndrome 5.

Where Pheochromocytoma/paraganglioma syndrome 5 variants cluster

• SDHB 4Fe-4S ferredoxin-type (positions 176–206): 11 of 48 disease-causing changes, 2.1× more than its size predicts.
• SDHC Transmembrane (positions 66–90): 5 of 16 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Pheochromocytoma/paraganglioma syndrome 5

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Uncertain variants in Pheochromocytoma/paraganglioma syndrome 5 that look disease-causing

Which prediction tools work for Pheochromocytoma/paraganglioma syndrome 5

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

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 98 out of 100
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 93 out of 100
• phyloP: 90 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/paraganglioma syndrome 5 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/paraganglioma syndrome 5 variants (7 disease-causing).
• Inherited phaeochromocytoma and paraganglioma excluding NF1 is also caused by SDHB variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (4 disease-causing).
• Mitochondrial complex II deficiency, nuclear type 1 is also caused by SDHA variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (18 disease-causing).
• Pheochromocytoma is also caused by SDHD variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (14 disease-causing).
• Paragangliomas with sensorineural hearing loss is also caused by SDHD variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (13 disease-causing).
• Carney-Stratakis syndrome is also caused by SDHD variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (11 disease-causing).
• Cowden syndrome is also caused by SDHD variants; they fall partly in the same places as the Pheochromocytoma/paraganglioma syndrome 5 variants (11 disease-causing).

Diseases related to Pheochromocytoma/paraganglioma syndrome 5

• Hereditary pheochromocytoma and paraganglioma, also linked to SDHA, SDHAF2, SDHB, SDHC and 1 more
• Gastrointestinal stromal tumor, also linked to SDHA, SDHB and SDHC
• Carney-Stratakis syndrome, also linked to SDHB, SDHC and SDHD
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to SDHA, SDHB and SDHC
• Pheochromocytoma, also linked to SDHB and SDHD
• Mitochondrial complex II deficiency, nuclear type 1, also linked to SDHA and SDHD
• Mitochondrial complex 2 deficiency, nuclear type 3, also linked to SDHB and SDHD
• Cowden syndrome, also linked to SDHD
• Paragangliomas with sensorineural hearing loss, also linked to SDHD
• Neurodegeneration with ataxia and late-onset optic atrophy, also linked to SDHA
• Familial isolated dilated cardiomyopathy, also linked to SDHA
• Dilated cardiomyopathy 1GG, also linked to SDHA

Frequently asked questions

Which genes are linked to Pheochromocytoma/paraganglioma syndrome 5?

In CATVariant, Pheochromocytoma/paraganglioma syndrome 5 is linked to 5 analyzed proteins: SDHB (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial), SDHC (Succinate dehydrogenase cytochrome b560 subunit, mitochondrial), SDHA (Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial), SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial) and SDHAF2 (Succinate dehydrogenase assembly factor 2, mitochondrial).

How many genetic variants are linked to Pheochromocytoma/paraganglioma syndrome 5?

1,970 variants: 82 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,802 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pheochromocytoma/paraganglioma syndrome 5 look disease-causing?

24 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SDHB W200C, SDHA R589Q, SDHB Q214H, SDHA G439R and SDHA G555R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Pheochromocytoma/paraganglioma syndrome 5?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 44 disease-causing and 9 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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