GeneBe

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 (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: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Pyruvate dehydrogenase E1-alpha deficiency; Leigh syndrome, X-linkedXLBiochemicalTherapy may not be effective in many individuals, but dietary (ketogenic diet) and medical (eg, thiamine) therapy may be beneficialBiochemical; Neurologic5786203; 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 (48 variants)
  • not provided (38 variants)
  • Inborn genetic diseases (7 variants)
  • Pyruvate dehydrogenase complex deficiency (6 variants)
  • SUDDEN INFANT DEATH SYNDROME (1 variants)
  • PDHA1-related disorder (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
2
clinvar
1
clinvar
2
clinvar
95
clinvar
7
clinvar
 107
missense
23
clinvar
36
clinvar
65
clinvar
11
clinvar
2
clinvar
 137
nonsense
9
clinvar
5
clinvar
2
clinvar
 16
start loss
0
frameshift
24
clinvar
5
clinvar
1
clinvar
1
clinvar
 31
inframe indel
4
clinvar
4
clinvar
8
clinvar
 16
splice donor/acceptor (+/-2bp)
9
clinvar
1
clinvar
1
clinvar
1
clinvar
 12
splice region
4
34
3
 41
non coding
1
clinvar
24
clinvar
88
clinvar
70
clinvar
 183
Total 71 53 103 196 79

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)914924
X-19343950-G-A Pyruvate dehydrogenase E1-alpha deficiency Benign (Apr 28, 2017)914925
X-19343959-C-T Pyruvate dehydrogenase E1-alpha deficiency Uncertain significance (Jan 13, 2018)914926
X-19344015-G-C Likely benign (Jun 18, 2018)392144
X-19344042-G-C Neurodevelopmental abnormality Likely benign (Apr 03, 2020)984575
X-19344052-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Aug 30, 2022)1541352
X-19344053-G-A Pyruvate dehydrogenase E1-alpha deficiency • Inborn genetic diseases Conflicting classifications of pathogenicity (Dec 18, 2023)803731
X-19344055-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Oct 24, 2022)1582407
X-19344058-C-G Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Oct 24, 2022)2036696
X-19344058-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Jan 18, 2024)1083903
X-19344059-G-A Inborn genetic diseases Uncertain significance (Dec 16, 2022)2336231
X-19344066-G-C Pyruvate dehydrogenase E1-alpha deficiency Pathogenic (Oct 01, 1995)10887
X-19344067-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Aug 25, 2023)1086532
X-19344068-G-A Uncertain significance (Dec 27, 2019)1311576
X-19344079-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Dec 12, 2023)1610869
X-19344081-CT-C Pyruvate dehydrogenase E1-alpha deficiency Likely pathogenic (Jan 03, 2022)1333508
X-19344084-C-T Pyruvate dehydrogenase E1-alpha deficiency Uncertain significance (Dec 07, 2023)2822006
X-19344091-G-A Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Mar 25, 2021)1544054
X-19344100-A-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Jan 29, 2024)756440
X-19344101-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Oct 23, 2023)2771251
X-19344102-C-A Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Jan 25, 2024)2102546
X-19344105-C-G Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Dec 11, 2023)1669589
X-19344110-C-T Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Sep 21, 2023)2734720
X-19344111-G-A Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Oct 17, 2023)2705861
X-19344111-G-C Pyruvate dehydrogenase E1-alpha deficiency Likely benign (Aug 18, 2023)3000032

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
PDHA1protein_codingprotein_codingENST00000379806 1217813
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.9880.0116125084011250850.00000400
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense2.57791750.4520.00001432796
Missense in Polyphen874.3820.107551130
Synonymous1.045666.80.8380.00000575825
Loss of Function3.70117.90.05600.00000152284

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.00006250.0000462
European (Non-Finnish)0.000.00
Middle Eastern0.000.00
South Asian0.000.00
Other0.000.00

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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