SDHC
protein-codingsuccinate dehydrogenase complex subunit C, the group of Mitochondrial complex II: succinate dehydrogenase subunits
Gene summary
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]
- PGL3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~48.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *SDHC* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The *SDHC* gene encodes the succinate dehydrogenase complex iron sulphur subunit C. Defects of this protein lead to complex II deficiency. This gene has also been implicated in autosomal dominant hereditary paraganglioma. This gene disease relationship has been assessed separately (https://search.clinicalgenome.org/kb/genes/HGNC:10682). However, after extensive literature review, no cases have been reported to have features consistent with primary mitochondrial disease. There is one mouse model (PMID: 31469588) with features that resemble primary mitochondrial disease, including lactic acidosis, hypoglycemia, circulating insulin decrease, weight loss, elevated CK, decreased muscle function, decline in activity, and, most importantly, protection from death by hypoxic conditioning. However, brain pathology did not reveal Leigh syndrome features and there was no direct biochemical evidence of complex II deficiency. In summary, there is no evidence for a causal role for *SDHC* variants in primary mitochondrial disease. This gene-disease association is not supported by experimental evidence and no reports have directly implicated the gene in individuals with primary mitochondrial disease to date. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 7, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0011719
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011544
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011740
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011719
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011544
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017366
Submitter: ClinGen
Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, as well as stabilization of the SDH complex. SDHC encodes one of the 4 subunits of SDH (succinate dehydrogenase), one of the two small integral membrane proteins in the mitochondrial complex II. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, this is a lumping Curation for SDHC and SDHC associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 3 (MIM: 605373) and Gastrointestinal stromal tumor (MIM: 606764). SDHC was first reported in relation to PGL/PCC in 2000 [Niemann and Muller et al., PMID: 11062460]. Three nonsense, two initiation codon, three missense, one splicing and one deletion variants are included in this curation [PMID: 11062460, 15342702, 29386252 and 16405730]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. Absent expression of SDHB, the iron protein, catalytic component of mitochondrial complex II were reported in 5 PGL/PCC patients carrying SDHC germline variants [PMIDs: 19576851 and 20236688]. Loss of the complex II SDH (succinate dehydrogenase) and SQR (succinate coenzyme Q oxidoreductase) enzyme activities were shown in Hela cells and Chinese hamster B9 cells transfected with two SDHC mutants, His127Ala and His127Tyr. The absence of SDH and SDR activities in SDHC targeted shRNA Hela and B9 cells can be rescued by wt SDHC construct, but not by the constructs of the two SDHC mutants [PMID: 19332149]. Knockout mouse homolog of human SDHC is homozygous-lethal [PubMed: 27626380]. In summary, the SDHC gene is definitely associated with autosomal dominant PGL/PCC syndrome. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0011740
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011544
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005086
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0017366
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Oncologic
Intervention: Oncologic
Rationale: The condition involves increased risk of certain types of neoplasms, and surveillance/early treatment of tumors (eg, surgical resection) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SDHC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003001.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 164 | 9 | 180 | ||
| missense | 2 | 20 | 388 | 7 | 1 | 418 |
| nonsense | 9 | 4 | 13 | |||
| start loss | 5 | 2 | 7 | |||
| frameshift | 30 | 6 | 5 | 1 | 42 | |
| splice donor/acceptor (+/-2bp) | 5 | 25 | 4 | 34 | ||
| Total | 51 | 57 | 404 | 172 | 10 | 694 |
Highest pathogenic variant AF is 0.000048328693
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002992.1 | 6 | MANE Select | |
| Ensembl | ENSP00000356953.3 | 6 | MANE Select | |
| RefSeq | NP_001030588.1 | 5 | Standard | |
| RefSeq | NP_001030589.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Citrate cycle (TCA cycle) - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
Biological Process
- tricarboxylic acid cycle
- mitochondrial electron transport, succinate to ubiquinone
- aerobic respiration
- oxidation-reduction process
Molecular Function
- succinate dehydrogenase (ubiquinone) activity
- electron transfer activity
- heme binding
- metal ion binding
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone)
- integral component of membrane
- respiratory chain complex II
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367975
- Coding exons
- 6
- Length
- 48938
- Individuals with no LoFs
- 125675
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125696
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.825 | 74 | 96.8 | 0.764 | 0.00000533 | 1081 |
| Missense (PolyPhen) | 18 | 29.002 | 0.62064 | 334 | ||
| Synonymous | -0.165 | 37 | 35.7 | 1.04 | 0.00000191 | 355 |
| Loss of Function | 0.990 | 7 | 10.5 | 0.669 | 6.19e-7 | 107 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00013 | 0.00012 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).;
- Disease
- DISEASE: Paragangliomas 3 (PGL3) [MIM:605373]: A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion. Paragangliomas can develop at various body sites, including the head, neck, thorax and abdomen. Most commonly, they are located in the head and neck region, specifically at the carotid bifurcation, the jugular foramen, the vagal nerve, and in the middle ear. {ECO:0000269|PubMed:11062460}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paraganglioma and gastric stromal sarcoma (PGGSS) [MIM:606864]: Gastrointestinal stromal tumors may be sporadic or inherited in an autosomal dominant manner, alone or as a component of a syndrome associated with other tumors, such as in the context of neurofibromatosis type 1 (NF1). Patients have both gastrointestinal stromal tumors and paragangliomas. Susceptibility to the tumors was inherited in an apparently autosomal dominant manner, with incomplete penetrance. {ECO:0000269|PubMed:17804857}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.354
Intolerance Scores
- LoFtool
- 0.335
- RVIS EVS
- 0.39
- RVIS percentile EVS
- 75.87
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.994
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |