TTPA

protein-coding

alpha tocopherol transfer protein

Gene summary

This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]

Previous symbols:

AVED

MANE transcript

NM_000370.3

Inheritance

ClinVar variants

P:105U:149B:152

Top phenotype

Ataxia with vitamin E deficiency

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr8:63,048,553-63,086,053

External References & Databases

Ensembl (ENSG00000137561)

Transcript & Mutation Effects

hg38 • Region Span ~37.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial isolated deficiency of vitamin ESUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: Orphanet

familial isolated deficiency of vitamin ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: PanelApp Australia

familial isolated deficiency of vitamin EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: G2P

familial isolated deficiency of vitamin EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: Myriad Women's Health

familial isolated deficiency of vitamin EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: Natera

familial isolated deficiency of vitamin ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010188

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ataxia with vitamin E deficiencyAR

Manifestation: Gastrointestinal; Neurologic

Intervention: Gastrointestinal

Rationale: Preventive treatment with vitamin E administration can ameliorate signs and symptoms of disease; Untreated, individuals typically present with neurological manifestations, including progressive ataxia, and knowledge can allow early treatment (which involves chronic supplementation with high-dose oral vitamin E, with the goal of maintaining plasma vitamin E concentrations in the high-normal range)

Refs: 4000224; 3361234; 7887897; 7719340; 8602747; 8972536; 463307; 10552255; 11554913; 12039660; 15300460; 20301419; 34663645

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTPA variants in ClinVar

11 Conditions Cataloged

not providedTotal: 366

Familial isolated deficiency of vitamin ETotal: 141

not specifiedTotal: 45

Inborn genetic diseasesTotal: 44

TTPA-related disorderTotal: 20

ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCYTotal: 6

Retinal dystrophyTotal: 4

CHD7-related CHARGE syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000370.3. 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	6 clinvar	148 clinvar	1 clinvar	156
missense		7 clinvar	140 clinvar	3 clinvar		150
nonsense	12 clinvar	8 clinvar	2 clinvar			22
start loss	1 clinvar	2 clinvar				3
frameshift	32 clinvar	28 clinvar				60
splice donor/acceptor (+/-2bp)	3 clinvar	11 clinvar	1 clinvar			15
Total	48	57	149	151	1	406

Highest pathogenic variant AF is 0.00017844353

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000370.3	RefSeq	NP_000361.1	5	MANE Select
ENST00000260116.5	Ensembl	ENSP00000260116.4	5	MANE Select
NM_001413414.1	RefSeq	NP_001400343.1	3	Standard
NM_001413415.1	RefSeq	NP_001400344.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ttpa	Danio rerio	Structure: immature eye Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

ttpa

Danio rerio

Structure: immature eye

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of fat-soluble vitamins
Metabolism
Metabolism of vitamins and cofactors
Vitamin E

Biological Process

embryonic placenta development
lipid metabolic process
response to nutrient
response to pH
response to toxic substance

Molecular Function

protein binding
phosphatidylinositol-4,5-bisphosphate binding
vitamin E binding
phosphatidylinositol-3,4-bisphosphate binding
intermembrane lipid transfer activity

Cellular Component

late endosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260116
Coding exons: 5
Length: 37501
Individuals with no LoFs: 125662
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125740
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.303	135	145	0.929	0.00000730	1800
Missense (PolyPhen)		49	52.808	0.92789		660
Synonymous	-0.142	56	54.7	1.02	0.00000267	547
Loss of Function	1.36	6	10.8	0.553	5.25e-7	127

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.000033	0.000033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells (PubMed:7887897). Binds both phosphatidylinol 3,4-bisphosphate and phosphatidylinol 4,5-bisphosphate; the resulting conformation change is important for the release of the bound alpha-tocopherol (By similarity). {ECO:0000250, ECO:0000269|PubMed:7887897}.;
Disease: DISEASE: Ataxia with isolated vitamin E deficiency (AVED) [MIM:277460]: An autosomal recessive disease characterized by undetectable or markedly reduced plasma levels of vitamin E, spinocerebellar degeneration, ataxia, areflexia and proprioception loss. {ECO:0000269|PubMed:15065857, ECO:0000269|PubMed:15300460, ECO:0000269|PubMed:7566022, ECO:0000269|PubMed:8602747, ECO:0000269|PubMed:9463307}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.589

Intolerance Scores

LoFtool: 0.478
RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.711

Gene Damage Prediction

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