PDHA1
pyruvate dehydrogenase E1 subunit alpha 1, the group of Pyruvate dehydrogenase complex
Basic information
Region (hg38): X:19343892-19361718
Previous symbols: [ "PDHA" ]
Links
Phenotypes
GenCC
Source:
- pyruvate dehydrogenase E1-alpha deficiency (Definitive), mode of inheritance: XLR
- pyruvate dehydrogenase E1-alpha deficiency (Definitive), mode of inheritance: XLD
- 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:
| 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
- Pyruvate dehydrogenase E1-alpha deficiency (376 variants)
- not provided (164 variants)
- Pyruvate dehydrogenase complex deficiency (37 variants)
- not specified (36 variants)
- Inborn genetic diseases (35 variants)
- PDHA1-related condition (2 variants)
- See cases (2 variants)
- MAP3K15-related condition (1 variants)
- Seizure;Epileptic encephalopathy (1 variants)
- Abnormality of the mitochondrion (1 variants)
- SUDDEN INFANT DEATH SYNDROME (1 variants)
- Neurodevelopmental delay (1 variants)
- Seizure;Intellectual disability (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.
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 | 84 | 96 | ||||
| missense | 21 | 38 | 64 | 133 | ||
| nonsense | 13 | |||||
| start loss | 0 | |||||
| frameshift | 24 | 29 | ||||
| inframe indel | 15 | |||||
| splice donor/acceptor (+/-2bp) | 11 | |||||
| splice region ? | 3 | 30 | 2 | 35 | ||
| non coding ? | 20 | 59 | 63 | 143 | ||
| Total | 67 | 51 | 98 | 152 | 72 |
Variants in PDHA1
This is a list of pathogenic ClinVar variants found in the PDHA1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| X-19343940-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Benign (Jan 12, 2018) | ||
| X-19343950-G-A | Pyruvate dehydrogenase E1-alpha deficiency | Benign (Apr 28, 2017) | ||
| X-19343959-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Uncertain significance (Jan 13, 2018) | ||
| X-19344015-G-C | Likely benign (Jun 18, 2018) | |||
| X-19344042-G-C | Neurodevelopmental abnormality | Likely benign (Apr 03, 2020) | ||
| X-19344052-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Aug 30, 2022) | ||
| X-19344053-G-A | Pyruvate dehydrogenase E1-alpha deficiency • Inborn genetic diseases | Conflicting classifications of pathogenicity (Dec 18, 2023) | ||
| X-19344055-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Oct 24, 2022) | ||
| X-19344058-C-G | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Oct 24, 2022) | ||
| X-19344058-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Jan 18, 2024) | ||
| X-19344059-G-A | Inborn genetic diseases | Uncertain significance (Dec 16, 2022) | ||
| X-19344066-G-C | Pyruvate dehydrogenase E1-alpha deficiency | Pathogenic (Oct 01, 1995) | ||
| X-19344067-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Aug 25, 2023) | ||
| X-19344068-G-A | Uncertain significance (Dec 27, 2019) | |||
| X-19344079-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Dec 12, 2023) | ||
| X-19344081-CT-C | Pyruvate dehydrogenase E1-alpha deficiency | Likely pathogenic (Jan 03, 2022) | ||
| X-19344084-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Uncertain significance (Aug 02, 2023) | ||
| X-19344091-G-A | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Mar 25, 2021) | ||
| X-19344100-A-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Jan 29, 2024) | ||
| X-19344101-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Oct 23, 2023) | ||
| X-19344102-C-A | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Jan 25, 2024) | ||
| X-19344105-C-G | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Dec 11, 2023) | ||
| X-19344110-C-T | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Sep 21, 2023) | ||
| X-19344111-G-A | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Oct 17, 2023) | ||
| X-19344111-G-C | Pyruvate dehydrogenase E1-alpha deficiency | Likely benign (Aug 18, 2023) |
GnomAD
Source:
| 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:
- 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