SDHD

protein-coding

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

Gene summary

This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

Previous symbols:

PGL
PGL1

MANE transcript

NM_003002.4

Inheritance

AR, AD

ClinVar variants

P:164U:386B:177

Top phenotype

Cowden syndrome 3; Paraganglioma and gastric stromal sarcoma; Pheochromocytoma/paraganglioma syndrome 1; Carcinoid tumors, intestinal; Mitochondrial complex II deficiency, nuclear type 3

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr11:112,086,824-112,120,016

External References & Databases

Ensembl (ENSG00000204370)

Transcript & Mutation Effects

hg38 • Region Span ~33.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex II deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009641

Submitter: Ambry Genetics

intestinal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005814

Submitter: G2P

hereditary pheochromocytoma-paragangliomaDEFINITIVE

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. 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 SDHD and SDHD associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 1 with or without deafness (MIM: 168000) and Pheochromocytoma (MIM: 171300). The autosomal recessive inherited Mitochondrial Complex II Deficiency (MIM: 252011) will be curated separately. SDHD encodes one of the subunits of SDH (succinate dehydrogenase), a component of complex II in mitochondria. It was the first tumor suppressor gene identified as encoding a mitochondrial protein. SDHD was first reported in relation to PGL/PCC in 2000 [Baysal et al., PMID: 10657297]. Two missense variants and seven nonsense variants from two large studies [PMID: 16317055 and 12000816] are included in this curation. Maternal transmission has been rarely reported and Dutch founder variants are recorded [PMIDs: 19584903, 11391798 and PMID: 15010701]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence showed absent or decreased expression of SDHB, the iron protein, catalytic component of mitochondrial complex II [PMIDs: 19576851, 20236688 and 14595761], and absent or decreased SDH enzyme activity [PMIDs 14595761 and 15652751] in human SDHD related tumors. There was no mouse model available as homozygous sdhd KO mice are embryonically lethal and heterozygous mice do not develop any tumors [PMIDs: 19956719, 15572694]. Biochemical studies on accumulated succinate due to reduced SDH activity and succinated induced pseudo-hypoxic drive, i.e., stabilization of HIF1a, inhibition of HIF prolyl hydroxylases are repetitively reported [PMIDs: 26971832, 17102089, 15987702]; in addition, SDHD related up-regulation of the p21WAF1/Cip1 in liver and kidney of the conditional tamoxifen-inducible SDHD-ESR mutant mice and two immortalized SDHD-ESR cell lines are also reported. The p21 is implicated in many biological processes including cell cycle, survival, and cancer [PMID: 24465590]. A truncated hSDHD mutant, W105X (previously W66X), expressed in immortalized Chinese hamster lung fibroblast model showed increased genomic instability mediated by increased ROS [PMID: 22041456]. In summary, the SDHD gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

Carney-Stratakis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011740

Submitter: Orphanet

renal cell carcinomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005086

Submitter: Genomics England PanelApp

mitochondrial complex II deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009641

Submitter: Orphanet

Carney-Stratakis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011740

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SDHD* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The *SDHD* gene encodes the succinate dehydrogenase (SDH, mitochondrial respiratory chain complex II) subunit D, an integral membrane protein that anchors the SDH enzyme to the matrix side of the mitochondrial inner membrane. Defects of this protein lead to complex II deficiency. The* SDHD* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24367056). While various names have been given to the constellation of features seen in those with autosomal recessive *SDHD*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the *SDHD* 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:10683). Evidence supporting the relationship between *SDHD* and primary mitochondrial disease includes case-level data and experimental data. This curation included two missense variants and one start-loss variant in two cases from two publications (PMIDs: 24367056, 26008905). This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction was recapitulated in a HEK293 knockout model (PMID: 34118887). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 4, 2022 (SOP Version 8).

pheochromocytoma/paraganglioma syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008192

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex 2 deficiency, nuclear type 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030937

Submitter: Ambry Genetics

Carney-Stratakis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011740

Submitter: Genomics England PanelApp

pheochromocytoma/paraganglioma syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008192

Submitter: Ambry Genetics

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: G2P

pheochromocytoma/paraganglioma syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008192

Submitter: G2P

mitochondrial complex II deficiency, nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cowden syndrome 3; Paraganglioma and gastric stromal sarcoma; Pheochromocytoma/paraganglioma syndrome 1; Carcinoid tumors, intestinal; Mitochondrial complex II deficiency, nuclear type 3AD/AR

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 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

Refs: 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

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SDHD variants in ClinVar

22 Conditions Cataloged

PheochromocytomaTotal: 659

Carney-Stratakis syndromeTotal: 656

Cowden syndrome 3Total: 654

Paragangliomas with sensorineural hearing lossTotal: 651

Hereditary cancer-predisposing syndromeTotal: 509

Pheochromocytoma/paraganglioma syndrome 1Total: 181

Hereditary pheochromocytoma and paragangliomaTotal: 161

not providedTotal: 150

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003002.4. 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			3 clinvar	148 clinvar	9 clinvar	160
missense	6 clinvar	30 clinvar	374 clinvar	19 clinvar	1 clinvar	430
nonsense	24 clinvar	4 clinvar	3 clinvar			31
start loss	5 clinvar					5
frameshift	47 clinvar	23 clinvar	3 clinvar			73
splice donor/acceptor (+/-2bp)	12 clinvar	13 clinvar	3 clinvar			28
Total	94	70	386	167	10	727

Highest pathogenic variant AF is 0.000030365978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003002.4	RefSeq	NP_002993.1	4	MANE Select
ENST00000375549.8	Ensembl	ENSP00000364699.3	4	MANE Select
NM_001276503.2	RefSeq	NP_001263432.1	3	Standard
NM_001276504.2	RefSeq	NP_001263433.1	3	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

Molecular Function

succinate dehydrogenase activity
succinate dehydrogenase (ubiquinone) activity
electron transfer activity
heme binding
metal ion binding

Cellular Component

mitochondrion
mitochondrial envelope
mitochondrial inner membrane
mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone)
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375549
Coding exons: 4
Length: 32857
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125747
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.166	90	85.7	1.05	0.00000429	1003
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.617

Intolerance Scores

LoFtool: 0.131
RVIS EVS: 0.46
RVIS percentile EVS: 78.16

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.746

Gene Damage Prediction

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