TIE1

Chr 1

tyrosine kinase with immunoglobulin like and EGF like domains 1

Also known as: JTK14, LMPHM11, TIE

NCBI Gene: 7075 ENSG00000066056 UniProt: P35590

This gene encodes a transmembrane tyrosine kinase that regulates angiogenesis and blood vessel stability by inhibiting angiopoietin 1 signaling through the endothelial receptor tyrosine kinase Tie2. Mutations cause lymphatic malformation 11, a vascular malformation disorder that follows autosomal dominant inheritance. The condition primarily affects the lymphatic vascular system, resulting in abnormal lymphatic vessel development and function.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the tyrosine protein kinase family. The encoded protein plays a critical role in angiogenesis and blood vessel stability by inhibiting angiopoietin 1 signaling through the endothelial receptor tyrosine kinase Tie2. Ectodomain cleavage of the encoded protein relieves inhibition of Tie2 and is mediated by multiple factors including vascular endothelial growth factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.89

Clinical Summary— TIE1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 171 VUS of 205 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 2.27

OE 0.68 (0.52–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.51Z-score

OE missense 0.84 (0.79–0.90)

615 obs / 729.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.52–0.89)

0≤0.351.4

Missense OE?0.84 (0.79–0.90)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 39 / 57.6Missense obs/exp: 615 / 729.9Syn Z: 1.53

This gene — mechanism propensity

0.7131th %ile

GOF

0.75top 25%

LOF

0.2874th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS171

Likely Benign9

Benign4

Pathogenic

171

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	2	168	1	0	171
Likely Benign	0	4	1	4	9
Benign	0	0	0	4	4
Total	2	174	2	8	186

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap TIE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →