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

ENSG00000073578 ∙ NCBI:6389 ∙ OMIM:600857 ∙ HGNC:10680 ∙ Uniprot:P31040 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
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 1	AD/AR	Biochemical; Cardiovascular; Gastrointestinal; Oncologic	For 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 beneficial	Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Oncologic	7550341; 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	508	7	523
missense	2	8	1100	4	1	1115
nonsense	41	8	1			50
start loss	6	4				10
frameshift	60	30	8			98
inframe indel			15			15
splice donor/acceptor (+/-2bp)	2	45	3	2		52
splice region		1	67	71	5	144
non coding			33	173	18	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)
5-218349-A-C		Paragangliomas 5 • not specified • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma • Leigh syndrome • Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Mar 01, 2024)
5-218351-C-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 01, 2024)
5-218351-C-T		Paragangliomas 5 • Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 15, 2023)
5-218351-C-CA		Hereditary cancer-predisposing syndrome	Uncertain significance (Jan 04, 2017)
5-218352-A-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 18, 2021)
5-218352-A-G		not specified • Leigh syndrome • Hereditary pheochromocytoma-paraganglioma • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary cancer-predisposing syndrome	Benign/Likely benign (Apr 14, 2021)
5-218352-A-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 29, 2020)
5-218353-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 08, 2022)
5-218353-G-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 09, 2022)
5-218353-G-T		Hereditary cancer-predisposing syndrome	Uncertain significance (May 20, 2023)
5-218354-A-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 14, 2022)
5-218354-A-T		Hereditary cancer-predisposing syndrome • Leigh syndrome • Mitochondrial complex II deficiency, nuclear type 1 • Hereditary pheochromocytoma-paraganglioma	Conflicting classifications of pathogenicity (Nov 28, 2023)
5-218354-AC-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 05, 2021)
5-218355-C-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jan 31, 2024)
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)
5-218355-CA-C		Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1	Pathogenic (Aug 17, 2023)
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)
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)
5-218356-A-T		Paragangliomas 5 • Paragangliomas 5;Mitochondrial complex II deficiency, nuclear type 1 • Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (Dec 30, 2023)
5-218357-T-A		Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Hereditary cancer-predisposing syndrome • Paragangliomas 5	Pathogenic (Nov 24, 2023)
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)
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)
5-218356-A-ATGTCGGGGGTCCGGGGCC		Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5	Uncertain significance (May 03, 2022)
5-218358-G-A		Hereditary cancer-predisposing syndrome • Mitochondrial complex II deficiency, nuclear type 1;Paragangliomas 5 • Paragangliomas 5	Pathogenic (Feb 06, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SDHA	protein_coding	protein_coding	ENST00000264932	15	38460

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.61e-10	0.972	125631	0	117	125748	0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.745	346	387	0.893	0.0000260	4262
Missense in Polyphen		139	179.81	0.77303		1899
Synonymous	-1.41	184	161	1.14	0.0000122	1339
Loss of Function	2.22	21	35.2	0.596	0.00000219	385

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000664	0.000658
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000749	0.000747
Middle Eastern	0.0000544	0.0000544
South Asian	0.000327	0.000294
Other	0.000326	0.000326

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

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

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