Mitochondrial complex II deficiency, nuclear type 1: genes and variants

Genes linked to Mitochondrial complex II deficiency, nuclear type 1

• 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.

  18 disease-causing and 1,136 uncertain variants in SDHA are linked to Mitochondrial complex II deficiency, nuclear type 1.

• 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.

  0 disease-causing and 0 uncertain variants in SDHD are linked to Mitochondrial complex II deficiency, nuclear type 1.

Known disease-causing variants in Mitochondrial complex II deficiency, nuclear type 1

Uncertain variants in Mitochondrial complex II deficiency, nuclear type 1 that look disease-causing

Which prediction tools work for Mitochondrial complex II deficiency, nuclear type 1

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

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 93 out of 100
• CADD: 91 out of 100
• SIFT: 90 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Mitochondrial complex II deficiency, nuclear type 1

• Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHA and SDHD
• Hereditary pheochromocytoma and paraganglioma, also linked to SDHA and SDHD
• Gastrointestinal stromal tumor, also linked to SDHA
• Cowden syndrome, also linked to SDHD
• Pheochromocytoma, also linked to SDHD
• Carney-Stratakis syndrome, also linked to SDHD
• Paragangliomas with sensorineural hearing loss, also linked to SDHD
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to SDHA
• Mitochondrial complex 2 deficiency, nuclear type 3, 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 Mitochondrial complex II deficiency, nuclear type 1?

In CATVariant, Mitochondrial complex II deficiency, nuclear type 1 is linked to 2 analyzed proteins: SDHA (Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial) and SDHD (Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial).

How many genetic variants are linked to Mitochondrial complex II deficiency, nuclear type 1?

1,174 variants: 18 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,136 are of uncertain significance or have conflicting reports.

Which uncertain variants in Mitochondrial complex II deficiency, nuclear type 1 look disease-causing?

5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SDHA R589Q, SDHA G439R, SDHA G555R, SDHA R554P and SDHA R554L. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Mitochondrial complex II deficiency, nuclear type 1?

Among tools not trained on clinical labels, phyloP separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 11 disease-causing and 10 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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