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

ENSG00000204370 ∙ NCBI:6392 ∙ OMIM:602690 ∙ HGNC:10683 ∙ Uniprot:O14521 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cowden syndrome 3; Paraganglioma and gastric stromal sarcoma; Pheochromocytoma/paraganglioma syndrome 1; Carcinoid tumors, intestinal; Mitochondrial complex II deficiency, nuclear type 3	AD/AR	Biochemical; Cardiovascular; Oncologic	In 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 beneficial	Biochemical; Cardiovascular; Neurologic; Oncologic	10657297; 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	83		86
missense	5	21	247	22		295
nonsense	22	3	3			28
start loss	4					4
frameshift	28	12	1			41
inframe indel		4	4			8
splice donor/acceptor (+/-2bp)	6	10	2			18
splice region	1	1	20	16	1	39
non coding			19	50	17	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)
11-112086899-A-C		Hereditary pheochromocytoma-paraganglioma	Likely benign (Aug 08, 2023)
11-112086900-G-A		SDHD-related disorder	Likely benign (Oct 05, 2020)
11-112086904-C-A			Uncertain significance (Dec 21, 2020)
11-112086904-C-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 24, 2023)
11-112086904-C-T		Hereditary cancer-predisposing syndrome • Hereditary pheochromocytoma-paraganglioma	Uncertain significance (Oct 17, 2023)
11-112086908-A-G		Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3 • Paragangliomas 1	Pathogenic (Feb 17, 2022)
11-112086908-A-T		Hereditary cancer-predisposing syndrome • Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Pheochromocytoma;Cowden syndrome 3	Pathogenic (Sep 10, 2023)
11-112086909-T-C		Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3	Pathogenic (May 08, 2023)
11-112086910-G-A		Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Cowden syndrome 3 • Hereditary cancer-predisposing syndrome	Pathogenic (Oct 25, 2022)
11-112086910-G-C		Paragangliomas 1 • Hereditary pheochromocytoma-paraganglioma • Hereditary cancer-predisposing syndrome • Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3	Pathogenic (Aug 04, 2023)
11-112086911-G-A		Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3	Uncertain significance (May 24, 2023)
11-112086912-C-A		Hereditary pheochromocytoma-paraganglioma	Uncertain significance (Nov 30, 2023)
11-112086912-C-G		Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Carney-Stratakis syndrome;Cowden syndrome 3	Uncertain significance (Jul 07, 2023)
11-112086912-C-T		Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3 • Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 21, 2022)
11-112086913-G-A		Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3;Pheochromocytoma	Likely benign (Aug 22, 2023)
11-112086913-G-C		Hereditary cancer-predisposing syndrome	Likely benign (Apr 07, 2020)
11-112086914-G-A		Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3	Uncertain significance (Feb 09, 2023)
11-112086914-G-C		Pheochromocytoma;Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Cowden syndrome 3	Uncertain significance (May 28, 2021)
11-112086914-G-T		Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3	Uncertain significance (Sep 25, 2020)
11-112086915-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 14, 2024)
11-112086915-TTC-T			Likely pathogenic (Mar 01, 2017)
11-112086916-T-A		Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3	Likely benign (Mar 13, 2017)
11-112086916-T-TC		Carney-Stratakis syndrome;Pheochromocytoma;Paragangliomas 1 • Carney-Stratakis syndrome;Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Cowden syndrome 3	Pathogenic (Jan 01, 2016)
11-112086917-C-A		Paragangliomas with sensorineural hearing loss;Pheochromocytoma;Carney-Stratakis syndrome;Cowden syndrome 3	Uncertain significance (Oct 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SDHD	protein_coding	protein_coding	ENST00000375549	4	32857

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.337	0.650	125744	0	3	125747	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.166	90	85.7	1.05	0.00000429	1003
Missense in Polyphen		18	22.856	0.78754		299
Synonymous	0.749	28	33.5	0.836	0.00000182	345
Loss of Function	2.09	2	8.61	0.232	5.26e-7	83

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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