SDHB
protein-codingsuccinate dehydrogenase complex iron sulfur subunit B, the group of Mitochondrial complex II: succinate dehydrogenase subunits
Gene summary
This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]
- SDH1
- SDH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016063
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009641
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011740
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017366
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011719
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0030974
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005086
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007273
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011719
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007273
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *SDHB* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The *SDHB* gene encodes the succinate dehydrogenase complex iron sulphur subunit B. Defects of this protein lead to complex II deficiency. The *SDHB* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22972948). While various names have been given to the constellation of features seen in those with autosomal recessive *SDHB*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the *SDHB* phenotype has been split, with one disease entity being autosomal recessive primary mitochondrial disease, according to the ClinGen Lumping and Splitting Framework. Of note, this gene has also been implicated in autosomal dominant hereditary pheochromocytoma-paraganglioma. This gene disease relationship has been assessed separately (https://search.clinicalgenome.org/kb/genes/HGNC:10681). Evidence supporting the relationship between *SDHB* and primary mitochondrial disease includes case-level data and experimental data. This curation included five missense variants in eight cases from five reports (PMIDs: 22972948, 26925370, 26642834, 27604842, 32124427). Of note, the c.143A>T (p.Asp48Val) was associated with disease in six probands, including four cases in a homozygous state and two cases in a compound heterozygous state. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction and developmental alterations associated with PMD were recapitulated in knockout animal models including round worm (*Caenorhabditis elegans*), fruit fly (*Drosophila melanogaster*) and zebrafish (*Danio rerio*) (PMIDs: 32859697, 17056719, 33156815). In summary, there is definitive evidence to support the relationship between *SDHB* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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:0011740
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011719
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011740
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007273
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008233
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, pheochromocytomas and gastrointestinal stromal tumors (GIST) including malignant PCC/PGLs 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. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, for SDHB, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability for tumor risk. Therefore, this is a lumping curation for SDHB and SDHB associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 4 (MIM: 115310), Gastrointestinal stromal tumor (MIM: 606764) and Pheochromocytoma (MIM: 171300). SDHB encodes the iron sulfur protein, one of the five subunits of SDH (succinate dehydrogenase), a component of complex II in mitochondria. SDHB was first reported in relation to PGL/PCC in 2001 [Astuti et al., PMID: 11404820]. Pathogenic variants in SDHB including frameshift, nonsense, missense (e.g. p.Pro197Arg, p.Val140Phe and p.Arg242His), splice site and large (exon) deletion variants were reported in the literature with incomplete penetrance and variable expressivity [PIMDs: 19389109, 19802898 and 25827221]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There is extensive experiment evidence including reduced or absent SDHB protein expression [PMID:19576851], reduced enzyme activity [PMID:22835832], increased succinate level, the hallmark of tumorigenesis in PGL and PCC, and increased nuclear expression of HIF1α (hypoxia inducible factor 1α) [PMID:15987702] in tumor cells of patients who carry germline SDHB variants. However, the knockout mouse homolog of human SDHB is homozygous-lethal [PMID 27626380]. In summary, the SDHB gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Neurologic; Oncologic
Intervention: Biochemical; Cardiovascular; Oncologic
Rationale: In conditions related to neoplasms, surveillance for and early diagnosis/treatment of associated neoplasms can be beneficial; In Mitochondrial complex II deficiency, nuclear type 4, medical management (eg, with riboflavin and coenzyme Q10) has been described, and individuals may have cardiac involvement such that surveillance may be beneficial
Comments: The proof for causation related to Cowden syndrome is unclear
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SDHB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003000.3. 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 | 1 | 5 | 249 | 14 | 269 | |
| missense | 20 | 103 | 633 | 19 | 1 | 776 |
| nonsense | 48 | 4 | 3 | 55 | ||
| start loss | 5 | 5 | ||||
| frameshift | 98 | 21 | 3 | 1 | 123 | |
| splice donor/acceptor (+/-2bp) | 18 | 29 | 3 | 1 | 51 | |
| Total | 189 | 158 | 647 | 269 | 16 | 1279 |
Highest pathogenic variant AF is 0.000023554265
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002991.2 | 8 | MANE Select | |
| Ensembl | ENSP00000364649.3 | 8 | MANE Select | |
| RefSeq | NP_001394290.1 | 8 | Standard | |
| Ensembl | ENSP00000481376.2 | 7 | 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
- succinate metabolic process
- aerobic respiration
- respiratory electron transport chain
Molecular Function
- protein binding
- succinate dehydrogenase (ubiquinone) activity
- electron transfer activity
- metal ion binding
- ubiquinone binding
Cellular Component
- nucleoplasm
- mitochondrion
- mitochondrial inner membrane
- mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone)
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375499
- Coding exons
- 8
- Length
- 35449
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125748
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.102 | 158 | 154 | 1.02 | 0.00000823 | 1825 |
| Missense (PolyPhen) | 59 | 69.509 | 0.84881 | 811 | ||
| Synonymous | 0.0242 | 52 | 52.2 | 0.996 | 0.00000253 | 520 |
| Loss of Function | 2.13 | 9 | 19.0 | 0.473 | 0.00000124 | 196 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Iron-sulfur protein (IP) 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: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:11404820, ECO:0000269|PubMed:12000816, ECO:0000269|PubMed:12618761, ECO:0000269|PubMed:14500403, ECO:0000269|PubMed:14974914, ECO:0000269|PubMed:15328326, ECO:0000269|PubMed:17634472}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Paragangliomas 4 (PGL4) [MIM:115310]: 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:11404820, ECO:0000269|PubMed:11897817, ECO:0000269|PubMed:14715873, ECO:0000269|PubMed:14974914, ECO:0000269|PubMed:15328326}. 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
- 0.636
Intolerance Scores
- LoFtool
- 0.140
- RVIS EVS
- 0.53
- RVIS percentile EVS
- 80.73
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.987
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |