GeneBe

KDR

protein-coding

kinase insert domain receptor, the group of V-set domain containing|CD molecules|Receptor tyrosine kinases|I-set domain containing

Gene summary

Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas. [provided by RefSeq, May 2009]

MANE transcript

NM_002253.4

Inheritance

AD, AR

ClinVar variants

P:3U:188B:39

Top phenotype

pulmonary arterial hypertension

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr4:55,078,481-55,125,595

External References & Databases

Ensembl (ENSG00000128052)NCBI Gene (3791)OMIM (191306)HGNC:6307GenCCUniProt (P35968)AlphaFoldClinVar (KDR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~47.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary arterial hypertensionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

KDR was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2018 by Graf et al., (PMID29650961). At least 6 loss of function variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data and experimental data. Summary of case level data: 3 points. Variants in this gene have been reported in at least 2 probands with a predicted or proven null variant (PMID: 31980491). Variants in this gene segregated with the disease in 2 additional family members with PAH. Summary of Case-Control Data: 3.5 points This gene-disease relationship has been studied in at least 1 case control study at the aggregate variant level. (PMID29650961). Protein truncating variants were reported in 4 out of 838 PAH cases versus 0 in 6385 controls. Both the case and the control group were analysed using whole genome sequencing. The gene-disease association is supported by animal models and expression studies. In summary, there is strong evidence to support the relationship between KDR and autosomal dominant pulmonary arterial hypertension. Three years must elapse from the first proposal of the association to reach a definitive classification.

tetralogy of fallotSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008542

Submitter: PanelApp Australia

tetralogy of fallotLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008542

Submitter: PanelApp Australia

pulmonary arterial hypertensionSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDR variants in ClinVar

14 Conditions Cataloged
not specifiedTotal: 139
not providedTotal: 54
Capillary infantile hemangiomaTotal: 17
Carcinoma of colonTotal: 14
KDR-related disorderTotal: 14
Tufted angioma of skinTotal: 2
High myopiaTotal: 1
TeratomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002253.4. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
15
clinvar
9
clinvar
 33
missense
1
clinvar
1
clinvar
166
clinvar
11
clinvar
4
clinvar
 183
nonsense
4
clinvar
 4
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
8
clinvar
 9
Total121882613230

Highest pathogenic variant AF is 0.00024970784

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002253.4RefSeqNP_002244.130MANE Select
ENST00000263923.5EnsemblENSP00000263923.430MANE Select
ENST00000922964.1EnsemblENSP00000593023.129Standard
ENST00000922964.2EnsemblENSP00000593023.129Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
kdrDanio rerio

Structure: intersegmental vessel

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • VEGF signaling pathway - Homo sapiens (human)
  • Fluid shear stress and atherosclerosis - Homo sapiens (human)
  • Rap1 signaling pathway - Homo sapiens (human)

Biological Process

  • angiogenesis
  • vasculogenesis
  • positive regulation of protein phosphorylation
  • positive regulation of endothelial cell proliferation
  • sprouting angiogenesis

Molecular Function

  • protein tyrosine kinase activity
  • transmembrane receptor protein tyrosine kinase activity
  • vascular endothelial growth factor-activated receptor activity
  • integrin binding
  • protein binding

Cellular Component

  • extracellular region
  • nucleus
  • endosome
  • early endosome
  • endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000263923
Coding exons
30
Length
47113
Individuals with no LoFs
125729
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125747
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.036597380.8940.00004038905
Missense (PolyPhen)178282.330.630483473
Synonymous-1.593132791.120.00001682594
Loss of Function6.731173.00.1510.00000387871

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000620.000062rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. {ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301, ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330, ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047, ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490, ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888, ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}.;
Disease
DISEASE: Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987, ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:18931684}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.;

Recessive Scores

pRec
0.131

Intolerance Scores

LoFtool
0.196
RVIS EVS
-1.14
RVIS percentile EVS
6.39

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.781

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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