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SDHD

succinate dehydrogenase complex subunit D, the group of Mitochondrial complex II: succinate dehydrogenase subunits

Basic information

Region (hg38): 11:112086823-112120016

Previous symbols: [ "PGL", "PGL1" ]

Links

ENSG00000204370NCBI:6392OMIM:602690HGNC:10683Uniprot:O14521AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • Carney-Stratakis syndrome (Strong), mode of inheritance: AD
  • renal cell carcinoma (Moderate), mode of inheritance: AD
  • Cowden disease (Supportive), mode of inheritance: AD
  • mitochondrial complex II deficiency (Supportive), mode of inheritance: AR
  • hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
  • Carney-Stratakis syndrome (Supportive), mode of inheritance: AD
  • paragangliomas 1 (Definitive), mode of inheritance: AD
  • mitochondrial complex II deficiency (Moderate), mode of inheritance: AR
  • mitochondrial complex II deficiency, nuclear type 1 (Strong), mode of inheritance: AR
  • Carney-Stratakis syndrome (Strong), mode of inheritance: AD
  • paragangliomas 1 (Strong), mode of inheritance: AD
  • mitochondrial disease (Limited), mode of inheritance: AR
  • hereditary pheochromocytoma-paraganglioma (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Cowden syndrome 3; Paraganglioma and gastric stromal sarcoma; Pheochromocytoma/paraganglioma syndrome 1; Carcinoid tumors, intestinal; Mitochondrial complex II deficiency, nuclear type 3AD/ARBiochemical; Cardiovascular; OncologicIn conditions related to neoplasms, surveillance for and early diagnosis/treatment of associated neoplasms can be beneficial; In Mitochondrial respiratory chain complex II deficiency, medical treatment (eg, with riboflavin, ubiquinol) may be beneficial, and individuals may have cardiac involvement such that surveillance may be beneficialBiochemical; Cardiovascular; Neurologic; Oncologic10657297; 11156372; 11526495; 11343322; 11519521; 12000816; 12205103; 12111639; 12007193; 12811540; 15032977; 15479192; 15328326; 16317055; 17848412; 17804857; 17667967; 18678321; 19239085; 19584903; 21348866; 21565294; 22261759; 22948026; 23072324; 23099648; 23322652; 24367056; 26008905

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SDHD gene.

  • Hereditary cancer-predisposing syndrome (292 variants)
  • not provided (110 variants)
  • Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Cowden syndrome 3 (58 variants)
  • Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Pheochromocytoma (49 variants)
  • Hereditary pheochromocytoma-paraganglioma (43 variants)
  • Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3 (41 variants)
  • Paragangliomas 1 (37 variants)
  • not specified (32 variants)
  • Mitochondrial complex 2 deficiency, nuclear type 3 (32 variants)
  • Cowden syndrome 3;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome (31 variants)
  • Carney-Stratakis syndrome;Cowden syndrome 3;Pheochromocytoma;Paragangliomas with sensorineural hearing loss (31 variants)
  • Pheochromocytoma (30 variants)
  • Cowden syndrome 3;Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss (26 variants)
  • Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3;Paragangliomas with sensorineural hearing loss (25 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 (24 variants)
  • Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3;Carney-Stratakis syndrome (22 variants)
  • Pheochromocytoma;Cowden syndrome 3;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome (20 variants)
  • Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 (20 variants)
  • Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Carney-Stratakis syndrome (19 variants)
  • Cowden syndrome 3;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma (19 variants)
  • Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Cowden syndrome 3;Pheochromocytoma (17 variants)
  • Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Carney-Stratakis syndrome;Pheochromocytoma (11 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3;Paragangliomas with sensorineural hearing loss (11 variants)
  • Pheochromocytoma;Cowden syndrome 3;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss (10 variants)
  • Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3 (9 variants)
  • Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3 (8 variants)
  • Carney-Stratakis syndrome;Cowden syndrome 3;Paragangliomas with sensorineural hearing loss;Pheochromocytoma (6 variants)
  • Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Pheochromocytoma;Carney-Stratakis syndrome (6 variants)
  • Cowden syndrome 3;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Pheochromocytoma (6 variants)
  • Cowden syndrome 3;Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss (5 variants)
  • Paragangliomas 3 (4 variants)
  • Carney-Stratakis syndrome (3 variants)
  • SDHD-related condition (3 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas 1 (3 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas 1;Cowden syndrome 3 (2 variants)
  • Pheochromocytoma;Paragangliomas 1 (2 variants)
  • Paragangliomas 1 with sensorineural hearing loss (2 variants)
  • Carney-Stratakis syndrome;Mitochondrial complex 2 deficiency, nuclear type 3;Pheochromocytoma;Paragangliomas 1 (2 variants)
  • Cowden syndrome 3 (2 variants)
  • Mitochondrial complex II deficiency, nuclear type 1 (2 variants)
  • Microcephaly (1 variants)
  • Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome;Paragangliomas 1 (1 variants)
  • Carney-Stratakis syndrome;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 1;Pheochromocytoma (1 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas 1;Mitochondrial complex 2 deficiency, nuclear type 3 (1 variants)
  • Carney-Stratakis syndrome;Pheochromocytoma;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 1 (1 variants)
  • Paragangliomas 4 (1 variants)
  • Pheochromocytoma;Paragangliomas 1;Cowden syndrome 3;Carney-Stratakis syndrome (1 variants)
  • Carney-Stratakis syndrome;Paragangliomas 1;Pheochromocytoma;Mitochondrial complex 2 deficiency, nuclear type 3 (1 variants)
  • Cowden syndrome 3;Carney-Stratakis syndrome;Paragangliomas 1;Pheochromocytoma (1 variants)
  • Pheochromocytoma;Mitochondrial complex 2 deficiency, nuclear type 3;Carney-Stratakis syndrome;Paragangliomas 1 (1 variants)
  • Inborn genetic diseases (1 variants)
  • Paragangliomas 1;Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3 (1 variants)
  • Pheochromocytoma;Cowden syndrome;Paragangliomas 1;Carney-Stratakis syndrome (1 variants)
  • Carotid body paraganglioma (1 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas 1 (1 variants)
  • Paraganglioma (1 variants)
  • Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss (1 variants)
  • Pheochromocytoma;Paragangliomas 1;Mitochondrial complex 2 deficiency, nuclear type 3;Carney-Stratakis syndrome (1 variants)
  • Carcinoid tumor of intestine (1 variants)
  • Cowden syndrome 3;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SDHD gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
3
clinvar
83
clinvar
86
missense
5
clinvar
21
clinvar
247
clinvar
22
clinvar
295
nonsense
22
clinvar
3
clinvar
3
clinvar
28
start loss
4
clinvar
4
frameshift
28
clinvar
12
clinvar
1
clinvar
41
inframe indel
4
clinvar
4
clinvar
8
splice donor/acceptor (+/-2bp)
6
clinvar
10
clinvar
2
clinvar
18
splice region
1
1
20
16
1
39
non coding
19
clinvar
50
clinvar
17
clinvar
86
Total 65 50 279 155 17

Highest pathogenic variant AF is 0.00000657

Variants in SDHD

This is a list of pathogenic ClinVar variants found in the SDHD region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
11-112086893-G-T Hereditary pheochromocytoma-paraganglioma Uncertain significance (Dec 13, 2023)3074801
11-112086899-A-C Hereditary pheochromocytoma-paraganglioma Likely benign (Aug 08, 2023)3072494
11-112086900-G-A SDHD-related condition Likely benign (Oct 05, 2020)3032176
11-112086904-C-A Uncertain significance (Dec 21, 2020)1320373
11-112086904-C-G Hereditary cancer-predisposing syndrome Uncertain significance (Jun 24, 2023)825357
11-112086904-C-T Hereditary cancer-predisposing syndrome • Hereditary pheochromocytoma-paraganglioma Uncertain significance (Oct 17, 2023)619913
11-112086908-A-G Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3 • Paragangliomas 1 Pathogenic (Feb 17, 2022)6911
11-112086908-A-T Hereditary cancer-predisposing syndrome • Cowden syndrome 3;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome Pathogenic (Sep 10, 2023)422629
11-112086909-T-C Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 Pathogenic (May 08, 2023)2925495
11-112086910-G-A Hereditary cancer-predisposing syndrome • Carney-Stratakis syndrome;Cowden syndrome 3;Pheochromocytoma;Paragangliomas with sensorineural hearing loss Pathogenic (Oct 25, 2022)579968
11-112086910-G-C Paragangliomas 1 • Hereditary pheochromocytoma-paraganglioma • Hereditary cancer-predisposing syndrome • Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3 Pathogenic (Aug 04, 2023)6906
11-112086911-G-A Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Carney-Stratakis syndrome;Pheochromocytoma Uncertain significance (May 24, 2023)646883
11-112086912-C-A Hereditary pheochromocytoma-paraganglioma Uncertain significance (Nov 30, 2023)3073916
11-112086912-C-G Carney-Stratakis syndrome;Cowden syndrome 3;Pheochromocytoma;Paragangliomas with sensorineural hearing loss Uncertain significance (Jul 07, 2023)579473
11-112086912-C-T Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3 • Hereditary cancer-predisposing syndrome Uncertain significance (Dec 21, 2022)852212
11-112086913-G-A Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3 Likely benign (Aug 22, 2023)766627
11-112086913-G-C Hereditary cancer-predisposing syndrome Likely benign (Apr 07, 2020)1756621
11-112086914-G-A Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 Uncertain significance (Feb 09, 2023)1367149
11-112086914-G-C Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 Uncertain significance (May 28, 2021)1424194
11-112086914-G-T Cowden syndrome 3;Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss Uncertain significance (Sep 25, 2020)465246
11-112086915-T-C Hereditary cancer-predisposing syndrome Uncertain significance (Feb 14, 2024)3223045
11-112086915-TTC-T Likely pathogenic (Mar 01, 2017)806737
11-112086916-T-A Cowden syndrome 3;Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss Likely benign (Mar 13, 2017)465248
11-112086916-T-TC Pheochromocytoma;Paragangliomas 1;Carney-Stratakis syndrome • Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Carney-Stratakis syndrome Pathogenic (Jan 01, 2016)239460
11-112086917-C-A Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3 Uncertain significance (Oct 29, 2023)2940872

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SDHDprotein_codingprotein_codingENST00000375549 432857
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.3370.650125744031257470.0000119
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.1669085.71.050.000004291003
Missense in Polyphen1822.8560.78754299
Synonymous0.7492833.50.8360.00000182345
Loss of Function2.0928.610.2325.26e-783

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.00005440.0000544
Finnish0.000.00
European (Non-Finnish)0.00001760.0000176
Middle Eastern0.00005440.0000544
South Asian0.000.00
Other0.000.00

dbNSFP

Source: dbNSFP

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). {ECO:0000250}.;
Disease
DISEASE: Paragangliomas 1 (PGL1) [MIM:168000]: A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion. PGL1 is a rare autosomal dominant disorder which is characterized by the development of mostly benign, highly vascular, slowly growing tumors in the head and neck. In the head and neck region, the carotid body is the largest of all paraganglia and is also the most common site of the tumors. {ECO:0000269|PubMed:10657297, ECO:0000269|PubMed:11343322, ECO:0000269|PubMed:11391796, ECO:0000269|PubMed:11391798, ECO:0000269|PubMed:15328326}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:11156372, ECO:0000269|PubMed:12000816, ECO:0000269|PubMed:15328326}. Note=Disease susceptibility is associated with variations 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.; DISEASE: Mitochondrial complex II deficiency (MT-C2D) [MIM:252011]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. {ECO:0000269|PubMed:24367056, ECO:0000269|PubMed:26008905}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
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);Oxidative phosphorylation - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Warburg Effect;Mitochondrial Electron Transport Chain;The oncogenic action of Succinate;The oncogenic action of Fumarate;Pyruvate dehydrogenase deficiency (E3);Pyruvate dehydrogenase deficiency (E2);2-ketoglutarate dehydrogenase complex deficiency;Mitochondrial complex II deficiency;Fumarase deficiency;Congenital lactic acidosis;Citric Acid Cycle;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Electron Transport Chain;TCA Cycle;Citrate cycle;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;Respiratory electron transport;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;TCA cycle;TCA cycle;Arginine Proline metabolism;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Tyrosine metabolism;Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. (Consensus)

Recessive Scores

pRec
0.617

Intolerance Scores

loftool
0.131
rvis_EVS
0.46
rvis_percentile_EVS
78.16

Haploinsufficiency Scores

pHI
0.205
hipred
Y
hipred_score
0.598
ghis
0.529

Essentials

essential_gene_CRISPR
E
essential_gene_CRISPR2
S
essential_gene_gene_trap
E
gene_indispensability_pred
E
gene_indispensability_score
0.746

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Sdhd
Phenotype
endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype;

Gene ontology

Biological process
tricarboxylic acid cycle;mitochondrial electron transport, succinate to ubiquinone
Cellular component
mitochondrion;mitochondrial envelope;mitochondrial inner membrane;mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone);integral component of membrane
Molecular function
succinate dehydrogenase activity;succinate dehydrogenase (ubiquinone) activity;electron transfer activity;heme binding;metal ion binding;ubiquinone binding