TPK1

protein-coding

thiamin pyrophosphokinase 1

Gene summary

The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine to thiamine pyrophosphate, a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]

MANE transcript

NM_022445.4

Inheritance

ClinVar variants

P:32U:108B:57

Top phenotype

Thiamine metabolism dysfunction syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr7:144,451,941-144,836,395

External References & Databases

Ensembl (ENSG00000196511)

Transcript & Mutation Effects

hg38 • Region Span ~384.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

childhood encephalopathy due to thiamine pyrophosphokinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013761

Submitter: Genomics England PanelApp

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TPK1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 10, 2020. The TPK1 gene encodes thiamine pyrophosphokinase 1, which catalyzes the conversion of thiamine to thiamine pyrophosphate (thiamine diphosphate or TDP). TDP is the metabolically active form of thiamine, which acts a cofactor of several thiamine-dependent enzymes in the cytosol, peroxisomes, and mitochondria. In the mitochondria, TDP acts as a cofactor of the pyruvate dehydrogenase complex. The TPK1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2011 (PMID: 22152682). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 variants identified in seven cases in six publications (PMIDs: 22152682, 25458521, 27896076, 30483896, 30789823, 31288420). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression data, and model systems (PMIDs: 31095747, 18853439, 31127358). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 10, 2020 (SOP Version 7).

childhood encephalopathy due to thiamine pyrophosphokinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013761

Submitter: Labcorp Genetics (formerly Invitae)

childhood encephalopathy due to thiamine pyrophosphokinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013761

Submitter: PanelApp Australia

childhood encephalopathy due to thiamine pyrophosphokinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013761

Submitter: Orphanet

Clinical Genomic Database (CGD)

Thiamine metabolism dysfunction syndrome 5AR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: In some individuals, thiamine supplementation appears to have beneficial effect (related compounds may be beneficial as well)

Refs: 22152682

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPK1 variants in ClinVar

6 Conditions Cataloged

Childhood encephalopathy due to thiamine pyrophosphokinase deficiencyTotal: 231

not providedTotal: 61

Inborn genetic diseasesTotal: 29

not specifiedTotal: 13

TPK1-related disorderTotal: 11

Leigh syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022445.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	55 clinvar		56
missense	3 clinvar	9 clinvar	106 clinvar	2 clinvar		120
nonsense	2 clinvar	1 clinvar				3
start loss	1 clinvar					1
frameshift	5 clinvar	2 clinvar				7
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	1 clinvar			10
Total	14	18	108	57	0	197

Highest pathogenic variant AF is 0.00010227788

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022445.4	RefSeq	NP_071890.2	8	MANE Select
ENST00000360057.7	Ensembl	ENSP00000353165.3	8	MANE Select
NM_001042482.2	RefSeq	NP_001035947.1	7	Standard
NM_001350879.1	RefSeq	NP_001337808.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thiamine metabolism - Homo sapiens (human)
Thiamine Metabolism
thiamin salvage III
Vitamin B1 (thiamin) metabolism
Metabolism

Biological Process

thiamine metabolic process
thiamine diphosphate biosynthetic process
phosphorylation
thiamine-containing compound metabolic process

Molecular Function

thiamine diphosphokinase activity
ATP binding
kinase activity
thiamine binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360057
Coding exons: 8
Length: 384455
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125747
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.342	121	132	0.916	0.00000655	1594
Missense (PolyPhen)		47	51.835	0.90672		613
Synonymous	0.340	44	47.0	0.937	0.00000250	446
Loss of Function	2.33	4	13.1	0.306	5.50e-7	167

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000067	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate. Can also catalyze the phosphorylation of pyrithiamine to pyrithiamine pyrophosphate. {ECO:0000269|PubMed:11342111}.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.322
RVIS EVS: 0.06
RVIS percentile EVS: 58.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.916

Gene Damage Prediction

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