PDHA1

pyruvate dehydrogenase E1 subunit alpha 1, the group of Pyruvate dehydrogenase complex

Basic information

Region (hg38): X:19343893-19361718

Previous symbols: [ "PDHA" ]

Links

ENSG00000131828 ∙ NCBI:5160 ∙ OMIM:300502 ∙ HGNC:8806 ∙ Uniprot:P08559 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pyruvate dehydrogenase E1-alpha deficiency (Strong), mode of inheritance: XL
• pyruvate dehydrogenase E1-alpha deficiency (Strong), mode of inheritance: AR
• pyruvate dehydrogenase E1-alpha deficiency (Supportive), mode of inheritance: XL
• Leigh syndrome with leukodystrophy (Supportive), mode of inheritance: AR
• pyruvate dehydrogenase E1-alpha deficiency (Strong), mode of inheritance: XL
• pyruvate dehydrogenase E1-alpha deficiency (Definitive), mode of inheritance: XL
• Leigh syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pyruvate dehydrogenase E1-alpha deficiency; Leigh syndrome, X-linked	XL	Biochemical	Therapy may not be effective in many individuals, but dietary (ketogenic diet) and medical (eg, thiamine) therapy may be beneficial	Biochemical; Neurologic	5786203; 4343503; 824610; 413346; 4050860; 2537010; 1293379; 1301207; 7692352; 7880337; 7808831; 8032855; 8199595; 8498846; 9727848; 10486093; 12379317; 12621116; 15138885; 18197404; 18398624; 18504677; 19517265; 19639391; 20002461; 20301764; 20462777; 21470495; 21914562; 23021068

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PDHA1 gene.

• Pyruvate_dehydrogenase_E1-alpha_deficiency (443 variants)
• not_provided (163 variants)
• Pyruvate_dehydrogenase_complex_deficiency (50 variants)
• Inborn_genetic_diseases (44 variants)
• not_specified (41 variants)
• PDHA1-related_disorder (10 variants)
• See_cases (3 variants)
• Epileptic_encephalopathy (1 variants)
• Neurodevelopmental_delay (1 variants)
• Intellectual_disability (1 variants)
• Abnormality_of_the_mitochondrion (1 variants)
• SUDDEN_INFANT_DEATH_SYNDROME (1 variants)
• Seizure (1 variants)
• Neurodevelopmental_abnormality (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PDHA1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000284.4. 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	3	4	107	6	122
missense	27	57	80	19	2	185
nonsense	11	7	4			22
start loss						0
frameshift	37	14	6	2		59
splice donor/acceptor (+/-2bp)	9	2	1	1		13
Total	86	83	95	129	8

Highest pathogenic variant AF is 0.0000113623

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PDHA1	protein_coding	protein_coding	ENST00000379806	12	17813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0116	125084	0	1	125085	0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.57	79	175	0.452	0.0000143	2796
Missense in Polyphen		8	74.382	0.10755		1130
Synonymous	1.04	56	66.8	0.838	0.00000575	825
Loss of Function	3.70	1	17.9	0.0560	0.00000152	284

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000625	0.0000462
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle. {ECO:0000269|PubMed:19081061, ECO:0000269|PubMed:7782287}.
• Disease: DISEASE: Pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170]: An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. {ECO:0000269|PubMed:1293379, ECO:0000269|PubMed:1338114, ECO:0000269|PubMed:1551669, ECO:0000269|PubMed:1909401, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:7545958, ECO:0000269|PubMed:7573035, ECO:0000269|PubMed:7757088, ECO:0000269|PubMed:7887409, ECO:0000269|PubMed:7967473, ECO:0000269|PubMed:8032855, ECO:0000269|PubMed:8199595, ECO:0000269|PubMed:8498846, ECO:0000269|PubMed:8504306, ECO:0000269|PubMed:8664900, ECO:0000269|PubMed:8844217, ECO:0000269|PubMed:9266390, ECO:0000269|PubMed:9671272}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Pyruvate metabolism - Homo sapiens (human);Glycolysis / Gluconeogenesis - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Warburg Effect;Pyruvate Dehydrogenase Complex Deficiency;Transfer of Acetyl Groups into Mitochondria;The oncogenic action of Succinate;The oncogenic action of Fumarate;Primary hyperoxaluria II, PH2;Pyruvate kinase deficiency;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;Leigh Syndrome;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;Pyruvate Metabolism;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency);TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc);Amino Acid metabolism;Lipid Metabolism Pathway;PI3K-AKT-mTOR - VitD3 Signalling;Hereditary Leiomyomatosis and Renal Cell Carcinoma Pathway;Acetylcholine Synthesis;Glycolysis and Gluconeogenesis;Signal Transduction;Regulation of pyruvate dehydrogenase (PDH) complex;Pyruvate metabolism;Pyruvate metabolism and Citric Acid (TCA) cycle;Metabolism of amino acids and derivatives;The citric acid (TCA) cycle and respiratory electron transport;Glycolysis and Gluconeogenesis;Metabolism;pyruvate decarboxylation to acetyl CoA;Glyoxylate metabolism and glycine degradation;Pyruvate metabolism;Signaling by Retinoic Acid;Signaling by Nuclear Receptors;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle (Consensus)

Recessive Scores

• pRec: 0.559

Intolerance Scores

• loftool: 0.0540
• rvis_EVS: 0.17
• rvis_percentile_EVS: 65.56

Haploinsufficiency Scores

• pHI: 0.278
• hipred: Y
• hipred_score: 0.619
• ghis: 0.493

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pdha1
• Phenotype: embryo 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); 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); reproductive system 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); growth/size/body region phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: glucose metabolic process;acetyl-CoA biosynthetic process from pyruvate;tricarboxylic acid cycle;mitochondrial acetyl-CoA biosynthetic process from pyruvate
• Cellular component: nucleus;nucleolus;mitochondrion;mitochondrial matrix;myelin sheath;pyruvate dehydrogenase complex
• Molecular function: pyruvate dehydrogenase activity;pyruvate dehydrogenase (acetyl-transferring) activity;protein binding;pyruvate dehydrogenase (NAD+) activity