SDHC

Chr 1ADIsolated cases

succinate dehydrogenase complex subunit C

Also known as: CYB560, CYBL, PGL3, PPGL3, QPS1, SDH3

NCBI Gene: 6391 ENSG00000143252 UniProt: Q99643 OMIM: 602413

SDHC encodes an integral membrane subunit of succinate dehydrogenase (mitochondrial complex II) that anchors the catalytic core to the inner mitochondrial membrane, functioning as a key enzyme in both the tricarboxylic acid cycle and aerobic respiration. Mutations cause autosomal dominant paraganglioma and pheochromocytoma syndrome 3, as well as gastrointestinal stromal tumors, through a dominant negative mechanism. The condition can also occur as isolated cases without family history.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/Isolated casesLOEUF 1.263 OMIM phenotypes

Clinical Summary— SDHC

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Gene-Disease Validity (ClinGen)

hereditary pheochromocytoma-paraganglioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.26LOEUF

pLI 0.000

Z-score 0.99

OE 0.67 (0.38–1.26)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.83Z-score

OE missense 0.76 (0.63–0.93)

74 obs / 96.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.38–1.26)

0≤0.351.4

Missense OE?0.76 (0.63–0.93)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 7 / 10.5Missense obs/exp: 74 / 96.8Syn Z: -0.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSDHC-related paragangliomasLOFAD

This gene — mechanism propensity

0.79top 25%

GOF

0.6346th %ile

LOF

0.2873th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFAn Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References