SDHA

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

Basic information

Region (hg38): 5:218303-257082

Previous symbols: [ "SDH2" ]

Links

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

Phenotypes

GenCC

Source: genCC

• pheochromocytoma/paraganglioma syndrome 5 (Strong), 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
• pheochromocytoma/paraganglioma syndrome 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
• pheochromocytoma/paraganglioma syndrome 5 (Strong), mode of inheritance: AD
• hereditary pheochromocytoma-paraganglioma (Definitive), mode of inheritance: AD
• Leigh syndrome (Moderate), mode of inheritance: AR
• dilated cardiomyopathy 1GG (Limited), mode of inheritance: AR
• mitochondrial complex II deficiency, nuclear type 1 (Definitive), mode of inheritance: AR
• pheochromocytoma/paraganglioma syndrome 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 (Limited), mode of inheritance: AD

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.

• Pheochromocytoma/paraganglioma_syndrome_5 (2573 variants)
• Mitochondrial_complex_II_deficiency,_nuclear_type_1 (2431 variants)
• Hereditary_cancer-predisposing_syndrome (1807 variants)
• not_provided (389 variants)
• Dilated_cardiomyopathy_1GG (324 variants)
• Neurodegeneration_with_ataxia_and_late-onset_optic_atrophy (122 variants)
• not_specified (91 variants)
• SDHA-related_disorder (86 variants)
• Leigh_syndrome (67 variants)
• Hereditary_pheochromocytoma-paraganglioma (51 variants)
• Gastrointestinal_stromal_tumor (24 variants)
• Rhabdomyosarcoma (2 variants)
• Intellectual_disability (2 variants)
• Carney_triad (2 variants)
• Sick_sinus_syndrome_2,_autosomal_dominant (2 variants)
• Paraganglioma (2 variants)
• Pulmonary_artery_atresia (2 variants)
• Incidental_Discovery (1 variants)
• Pheochromocytoma (1 variants)
• Cancer_or_benign_tumor (1 variants)
• Skeletal_myopathy (1 variants)
• Neoplasm_of_brain (1 variants)
• Primary_dilated_cardiomyopathy (1 variants)
• Diffuse_midline_glioma,_H3_K27-altered (1 variants)
• Dystonia,_early-onset,_and/or_spastic_paraplegia (1 variants)
• Hereditary_renal_cell_carcinoma (1 variants)
• B-lymphoblastic_leukemia/lymphoma_with_hypodiploidy (1 variants)
• Pheochromocytoma/paraganglioma_syndrome_4 (1 variants)
• See_cases (1 variants)
• Pheochromocytoma/paraganglioma_syndrome_1 (1 variants)
• Opsoclonus-myoclonus_syndrome (1 variants)
• Diffuse_pediatric-type_high-grade_glioma,_H3-wildtype_and_IDH-wildtype (1 variants)
• Childhood_neoplasm (1 variants)
• Multiple_endocrine_neoplasia_type_2A (1 variants)
• Pilocytic_astrocytoma (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. These statistics are base on transcript: NM_000004168.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	1	14	649	43	709
missense	9	36	1428	47	1	1521
nonsense	55	11	1			67
start loss	8	3				11
frameshift	111	39	10			160
splice donor/acceptor (+/-2bp)	3	70	8	2		83
Total	188	160	1461	698	44

Highest pathogenic variant AF is 0.0004034707

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