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SDHA

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

Basic information

Region (hg38): 5:218302-257082

Previous symbols: [ "SDH2" ]

Links

ENSG00000073578NCBI:6389OMIM:600857HGNC:10680Uniprot:P31040AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • Leigh syndrome (Definitive), mode of inheritance: AR
  • paragangliomas 5 (Moderate), mode of inheritance: AD
  • Leigh syndrome (Moderate), mode of inheritance: AR
  • familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
  • mitochondrial complex II deficiency (Supportive), mode of inheritance: AR
  • hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
  • gastrointestinal stromal tumor (Supportive), mode of inheritance: AD
  • Leigh syndrome with leukodystrophy (Supportive), mode of inheritance: AR
  • paragangliomas 5 (Definitive), mode of inheritance: AD
  • mitochondrial complex II deficiency, nuclear type 1 (Strong), mode of inheritance: AR
  • neurodegeneration with ataxia and late-onset optic atrophy (Strong), mode of inheritance: AD
  • paragangliomas 5 (Strong), mode of inheritance: AD
  • hereditary pheochromocytoma-paraganglioma (Definitive), mode of inheritance: AD
  • Leigh syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Pheochromocytoma/paraganglioma syndrome 5; Gastrointestinal stromal tumors; Cardiomyopathy, dilated, 1GG; Neurodegeneration with ataxia and late-onset optic atrophy; Mitochondrial respiratory chain complex II deficiency, nuclear type 1AD/ARBiochemical; Cardiovascular; Gastrointestinal; OncologicFor conditions that involve increased risk of neoplasms, awareness and surveillance may allow early diagnosis and treatment (eg, via surgical management), which may improve outcomes; In conditions such as Cardiomyopathy, dilated, Neurodegeneration with ataxia and late-onset optic atrophy; and Mitochondrial respiratory chain complex II deficiency, nuclear type 1, recognition of cardiovascular disease may allow early medical management, which may be helpful to help decrease morbidity; 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; Musculoskeletal; Neurologic; Oncologic7550341; 8967754; 10746566; 10976639; 12794685; 16737791; 16798039; 20484225; 20551992; 21505157; 22972948; 23322652; 27683074

ClinVar

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

  • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 (1371 variants)
  • Hereditary cancer-predisposing syndrome (1274 variants)
  • Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 (580 variants)
  • not provided (288 variants)
  • Dilated cardiomyopathy 1GG (159 variants)
  • Paragangliomas 5 (152 variants)
  • Mitochondrial complex II deficiency, nuclear type 1 (96 variants)
  • not specified (90 variants)
  • Leigh syndrome (75 variants)
  • Hereditary pheochromocytoma-paraganglioma (68 variants)
  • Gastrointestinal stromal tumor (20 variants)
  • SDHA-related condition (18 variants)
  • Neurodegeneration with ataxia and late-onset optic atrophy (15 variants)
  • Paragangliomas 5;Neurodegeneration with ataxia and late-onset optic atrophy;Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG (9 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Neurodegeneration with ataxia and late-onset optic atrophy;Dilated cardiomyopathy 1GG (7 variants)
  • Inborn genetic diseases (7 variants)
  • Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Neurodegeneration with ataxia and late-onset optic atrophy (7 variants)
  • Paragangliomas 5;Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1;Neurodegeneration with ataxia and late-onset optic atrophy (5 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG;Neurodegeneration with ataxia and late-onset optic atrophy;Paragangliomas 5 (4 variants)
  • SDHA-Related Disorders (4 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Neurodegeneration with ataxia and late-onset optic atrophy;Dilated cardiomyopathy 1GG;Paragangliomas 5 (4 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Dilated cardiomyopathy 1GG;Neurodegeneration with ataxia and late-onset optic atrophy (4 variants)
  • Leigh syndrome;Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG (3 variants)
  • Dilated cardiomyopathy 1GG;Neurodegeneration with ataxia and late-onset optic atrophy;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 (3 variants)
  • Leigh syndrome;Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG;Paragangliomas 5 (3 variants)
  • Dilated cardiomyopathy 1GG;Neurodegeneration with ataxia and late-onset optic atrophy;Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 (2 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Leigh syndrome;Dilated cardiomyopathy 1GG;Paragangliomas 5 (2 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Leigh syndrome;Paragangliomas 5;Dilated cardiomyopathy 1GG (2 variants)
  • Rhabdomyosarcoma (2 variants)
  • Paragangliomas 5;Neurodegeneration with ataxia and late-onset optic atrophy;Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1 (2 variants)
  • Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG;Neurodegeneration with ataxia and late-onset optic atrophy (2 variants)
  • Pulmonary artery atresia (2 variants)
  • Paragangliomas 5;Leigh syndrome;Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1 (2 variants)
  • Pheochromocytoma (1 variants)
  • Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1 variants)
  • See cases (1 variants)
  • Multiple endocrine neoplasia, type 2a (1 variants)
  • Skeletal myopathy (1 variants)
  • Opsoclonus-myoclonus syndrome (1 variants)
  • Dilated cardiomyopathy 1GG;Leigh syndrome;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 (1 variants)
  • Diffuse midline glioma, H3 K27-altered (1 variants)
  • Primary dilated cardiomyopathy (1 variants)
  • Neurodegeneration with ataxia and late-onset optic atrophy;Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG (1 variants)
  • Leigh syndrome;Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 (1 variants)
  • Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Leigh syndrome (1 variants)
  • Dilated cardiomyopathy 1GG;Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1;Neurodegeneration with ataxia and late-onset optic atrophy (1 variants)
  • Carney triad (1 variants)
  • Hereditary pheochromocytoma-paraganglioma;Gastrointestinal stromal tumor;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 (1 variants)
  • Hereditary renal cell carcinoma (1 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Dilated cardiomyopathy 1GG;Leigh syndrome (1 variants)
  • Neurodegeneration with ataxia and late-onset optic atrophy;Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5;Dilated cardiomyopathy 1GG (1 variants)
  • Pheochromocytoma;Paraganglioma (1 variants)
  • Leigh syndrome;Dilated cardiomyopathy 1GG (1 variants)
  • Pilocytic astrocytoma (1 variants)
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy (1 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG;Paragangliomas 5 (1 variants)
  • Mitochondrial complex II deficiency, nuclear type 1;Dilated cardiomyopathy 1GG;Paragangliomas 5;Neurodegeneration with ataxia and late-onset optic atrophy (1 variants)
  • Dilated cardiomyopathy 1GG;Mitochondrial complex II deficiency, nuclear type 1;Neurodegeneration with ataxia and late-onset optic atrophy;Paragangliomas 5 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SDHA 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
8
clinvar
508
clinvar
7
clinvar
523
missense
2
clinvar
8
clinvar
1100
clinvar
4
clinvar
1
clinvar
1115
nonsense
41
clinvar
8
clinvar
1
clinvar
50
start loss
6
clinvar
4
clinvar
10
frameshift
60
clinvar
30
clinvar
8
clinvar
98
inframe indel
15
clinvar
15
splice donor/acceptor (+/-2bp)
2
clinvar
45
clinvar
3
clinvar
2
clinvar
52
splice region
1
67
71
5
144
non coding
33
clinvar
173
clinvar
18
clinvar
224
Total 111 95 1168 687 26

Highest pathogenic variant AF is 0.0000263

Variants in SDHA

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

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

Position Type Phenotype Significance ClinVar
5-218320-A-AGGGACTGGC Paragangliomas 5 Benign (Nov 06, 2023)2673969
5-218349-A-C Paragangliomas 5 • not specified • Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma • Leigh syndrome • Hereditary cancer-predisposing syndrome Conflicting classifications of pathogenicity (Mar 01, 2024)371942
5-218351-C-G Hereditary cancer-predisposing syndrome Uncertain significance (Feb 01, 2024)3223751
5-218351-C-T Paragangliomas 5 • Hereditary cancer-predisposing syndrome Uncertain significance (Jul 15, 2023)371867
5-218351-C-CA Hereditary cancer-predisposing syndrome Uncertain significance (Jan 04, 2017)486398
5-218352-A-C Hereditary cancer-predisposing syndrome Uncertain significance (Feb 18, 2021)1744677
5-218352-A-G not specified • Leigh syndrome • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma • Hereditary cancer-predisposing syndrome Benign/Likely benign (Apr 14, 2021)259243
5-218352-A-T Hereditary cancer-predisposing syndrome Uncertain significance (Jul 29, 2020)1744685
5-218353-G-A Hereditary cancer-predisposing syndrome Uncertain significance (Mar 08, 2022)1736905
5-218353-G-C Hereditary cancer-predisposing syndrome Uncertain significance (Dec 09, 2022)824486
5-218353-G-T Hereditary cancer-predisposing syndrome Uncertain significance (May 20, 2023)486369
5-218354-A-G Hereditary cancer-predisposing syndrome Uncertain significance (Jul 14, 2022)1798646
5-218354-A-T Hereditary cancer-predisposing syndrome • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma • Leigh syndrome Conflicting classifications of pathogenicity (Nov 28, 2023)486359
5-218354-AC-A Hereditary cancer-predisposing syndrome Uncertain significance (Feb 05, 2021)1784203
5-218355-C-G Hereditary cancer-predisposing syndrome Uncertain significance (Jan 31, 2024)1784187
5-218355-C-T Leigh syndrome • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma • Hereditary cancer-predisposing syndrome Conflicting classifications of pathogenicity (Jan 09, 2024)353200
5-218355-CA-C Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 Pathogenic (Aug 17, 2023)426781
5-218356-A-C Mitochondrial complex II deficiency, nuclear type 1 • Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 • Hereditary cancer-predisposing syndrome • Neurodegeneration with ataxia and late-onset optic atrophy • Paragangliomas 5 Pathogenic (Nov 19, 2023)8744
5-218356-A-G Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Hereditary cancer-predisposing syndrome • Paragangliomas 5 Pathogenic/Likely pathogenic (Feb 06, 2024)239661
5-218356-A-T Paragangliomas 5 • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Hereditary cancer-predisposing syndrome Pathogenic/Likely pathogenic (Dec 30, 2023)371794
5-218357-T-A Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Hereditary cancer-predisposing syndrome • Paragangliomas 5 Pathogenic (Nov 24, 2023)582115
5-218357-T-C Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Paragangliomas 5 • Hereditary cancer-predisposing syndrome Pathogenic/Likely pathogenic (Dec 05, 2023)412398
5-218357-T-G Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Rhabdomyosarcoma • Mitochondrial complex II deficiency, nuclear type 1;Neurodegeneration with ataxia and late-onset optic atrophy;Paragangliomas 5;Dilated cardiomyopathy 1GG • Hereditary cancer-predisposing syndrome • Paragangliomas 5 Pathogenic/Likely pathogenic (Feb 06, 2024)422382
5-218356-A-ATGTCGGGGGTCCGGGGCC Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 Uncertain significance (May 03, 2022)2132819
5-218358-G-A Hereditary cancer-predisposing syndrome • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Paragangliomas 5 Pathogenic (Feb 06, 2024)2562379

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SDHAprotein_codingprotein_codingENST00000264932 1538460
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
2.61e-100.97212563101171257480.000465
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.7453463870.8930.00002604262
Missense in Polyphen139179.810.773031899
Synonymous-1.411841611.140.00001221339
Loss of Function2.222135.20.5960.00000219385

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0006640.000658
Ashkenazi Jewish0.000.00
East Asian0.00005440.0000544
Finnish0.0001850.000185
European (Non-Finnish)0.0007490.000747
Middle Eastern0.00005440.0000544
South Asian0.0003270.000294
Other0.0003260.000326

dbNSFP

Source: dbNSFP

Function
FUNCTION: Flavoprotein (FP) 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) (PubMed:24781757). Can act as a tumor suppressor (PubMed:20484225). {ECO:0000269|PubMed:20484225, ECO:0000305|PubMed:24781757}.;
Disease
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. Note=The disease is caused by mutations affecting the gene represented in this entry. {ECO:0000269|PubMed:12794685}.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:10746566, ECO:0000269|PubMed:24781757, ECO:0000269|PubMed:7550341}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1GG (CMD1GG) [MIM:613642]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:20551992}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paragangliomas 5 (PGL5) [MIM:614165]: 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:20484225}. 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 and Deficiency of Pyruvate Dehydrogenase complex (PDHc);fig-met-1-last-solution;Amino Acid metabolism;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)

Intolerance Scores

loftool
0.432
rvis_EVS
-0.86
rvis_percentile_EVS
10.95

Haploinsufficiency Scores

pHI
0.296
hipred
Y
hipred_score
0.590
ghis
0.497

Essentials

essential_gene_CRISPR
E
essential_gene_CRISPR2
E
essential_gene_gene_trap
E
gene_indispensability_pred
E
gene_indispensability_score
0.983

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Sdha
Phenotype
homeostasis/metabolism phenotype; 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);

Gene ontology

Biological process
tricarboxylic acid cycle;succinate metabolic process;mitochondrial electron transport, succinate to ubiquinone;nervous system development;respiratory electron transport chain;oxidation-reduction process
Cellular component
nucleolus;mitochondrion;mitochondrial inner membrane;mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone);myelin sheath;plasma membrane succinate dehydrogenase complex
Molecular function
succinate dehydrogenase activity;protein binding;succinate dehydrogenase (ubiquinone) activity;electron transfer activity;flavin adenine dinucleotide binding