GeneBe

FLT4

protein-coding

fms related receptor tyrosine kinase 4, the group of Receptor tyrosine kinases|I-set domain containing

Gene summary

This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]

MANE transcript

NM_182925.5

Inheritance

AD, AR

ClinVar variants

P:80U:311B:136

Top phenotype

Lymphatic malformation 1; Congenital heart defects, multiple types, 7

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr5:180,601,506-180,649,624

External References & Databases

Ensembl (ENSG00000037280)NCBI Gene (2324)OMIM (136352)HGNC:3767GenCCUniProt (P35916)AlphaFoldClinVar (FLT4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~48.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphatic malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007919

Submitter: ClinGen

FLT4 (formerly VEGFR3) encodes a tyrosine kinase receptor that plays a role in angiogenesis and lymphangiogenesis and was first reported in relation to autosomal dominant Lymphatic malformation 1 (Milroy disease) in 2000 (Karkkainen MJ et al., Irrthum A et al.) and autosomal dominant congenital heart defects in 2017 (Jin et al., PMID: 28991257). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) and phenotypic variability between reported phenotypic assertions. Therefore, the following disease entities have been split into multiple disease entities; Lymphatic malformation (OMIM:153100) and Congenital heart defects, multiple types, 7 (OMIM:618780). The split curation for autosomal dominant Congenital heart defects, multiple types, 7 has been performed separately. Lymphatic malformation 1 is primarily characterized by bilateral lower-limb lymphedema with inter and intra-familial variability, hydrocele in males, prominent (varicose) veins below the knees, and dysplastic toenails. Prenatal manifestations may include pedal edema, mild pleural effusions, and rarely non-immune fetal hydrops. Sixteen probands including 5 prenatal presentations are included in this curation along with affected family members (n = ~75) (PMIDs: 10835628, 10856194, 12960217, 16231305, 17250670, 18719607, 16965327, 23074044, 33027564, 34103024). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. To date, only nonsynonymous and in-frame deletion variants located in the exons encoding for the tyrosine kinase domain (aa 845-1173) have been reported, and affected individuals were not reported to have congenital heart defects. This gene-disease relationship is also supported by experimental evidence; expression studies demonstrating lymphatic endothelial expression (PMIDs: 7724599, 8245783), in vitro functional assays demonstrating abolished tyrosine kinase autophosphorylation and downstream target phosphorylation (PMIDs: 10835628, 10856194), and animal models demonstrating the phenotypes reported in humans (PMIDs: 11175851, 11592985). In summary, FLT4 is definitively associated with autosomal dominant Lymphatic malformation 1. This has been repeatedly demonstrated in both clinical diagnostic and research settings, and has been upheld over time.

tetralogy of fallotSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008542

Submitter: Orphanet

lymphatic malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007919

Submitter: PanelApp Australia

lymphatic malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007919

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart defects, multiple types, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032913

Submitter: G2P

congenital heart defects, multiple types, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032913

Submitter: Labcorp Genetics (formerly Invitae)

lymphatic malformationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019313

Submitter: Orphanet

lymphatic malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007919

Submitter: Ambry Genetics

congenital heart defects, multiple types, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032913

Submitter: PanelApp Australia

congenital heart defects, multiple types, 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032913

Submitter: ClinGen

FLT4 (formerly VEGFR3) encodes a tyrosine kinase receptor that plays a role in angiogenesis and lymphangiogenesis and was first reported in relation to autosomal dominant Lymphatic malformation 1 (Milroy disease) in 2000 (Karkkainen MJ et al., Irrthum A et al.) and autosomal dominant congenital heart defects in 2017 (Jin et al., PMID: 28991257). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) (LoF vs GoF) and phenotypic variability between reported phenotypic assertions. Therefore, the following disease entities have been split into multiple disease entities; Congenital heart defects, multiple types, 7 (OMIM:618780) and Lymphatic malformation 1 (OMIM:153100). The split curation for autosomal dominant Lymphatic malformation 1 (OMIM:153100) has been performed separately by Prenatal GCEP. Congenital heart defects, multiple types, 7 is primarily characterized by tetralogy of Fallot (ToF) usually accompanied by pulmonary atresia, which might show incomplete penetrance in variant carriers. Seven probands including 2 prenatal presentations are included in this curation along with affected family members (PMIDs: 28991257, 30232381, 33142350, 34905512) in addition to a large case-control study reporting statistically significant enrichment of heterozygous loss-of-function variants in individuals with ToF compared to ethnically matched individuals without ToF (PMID: 30582441). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. To date no individual was reported to have lymphedema (predominantly in the lower extremities) observed in Lymphatic malformation 1 (Milroy disease). There is no data yet to assess whether there is an increased risk for lymphedema (i.e. chylothorax) development before or after surgery in individuals carrying loss-of-function FLT variants. This gene-disease relationship is also preliminarily supported by experimental evidence; expression studies in fetal tissue samples demonstrating expression in the epicardium and endothelia of the large blood vessels (PMIDs: 8245783) and knockout mice lacking the intact FLT4 gene demonstrating a defect in the vasculature formation that is not compatible with life (PMIDs: 9794766). Of note, heterozygous mice models are phenotypically and embryonically normal, however, zygosity discrepancy between humans and animal models is not uncommon. In summary, there is definitive evidence to support the relationship between FLT4 and autosomal dominant Congenital heart defects, multiple types, 7. This has been repeatedly demonstrated in the clinical diagnostic settings and supported by preliminary experimental evidence. This classification was approved by the Prenatal GCEP on 12/14/2022 (SOP version 9).

capillary infantile hemangiomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011191

Submitter: Genomics England PanelApp

lymphatic malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007919

Submitter: G2P

Clinical Genomic Database (CGD)

Lymphatic malformation 1; Congenital heart defects, multiple types, 7AD/AR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: In Lymphatic malformation, treatment includes early and aggressive treatment of infections, as well as prophylactic antibiotics in some instances; Individuals with congenital cardiac anomalies may benefit from early diagnosis to enable early surgical and other interventions

Comments: Biallelic inheritance has been described

Refs: 14295660; 9817924; 10835628; 12960217; 15689446; 16965327; 16924388; 19002718; 19289394; 20301417; 22768468; 28991257; 30232381Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FLT4 variants in ClinVar

17 Conditions Cataloged
not providedTotal: 223
Inborn genetic diseasesTotal: 152
not specifiedTotal: 94
FLT4-related disorderTotal: 92
Hereditary lymphedema type ITotal: 65
Congenital heart defects, multiple types, 7Total: 41
Carcinoma of colonTotal: 22
Capillary infantile hemangiomaTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182925.5. 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
1
clinvar
7
clinvar
78
clinvar
7
clinvar
 93
missense
14
clinvar
29
clinvar
290
clinvar
44
clinvar
6
clinvar
 383
nonsense
10
clinvar
5
clinvar
1
clinvar
 16
start loss
0
frameshift
8
clinvar
8
clinvar
8
clinvar
 24
splice donor/acceptor (+/-2bp)
3
clinvar
2
clinvar
5
clinvar
1
clinvar
 11
Total354531112313527

Highest pathogenic variant AF is 0.000013135426

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_182925.5RefSeqNP_891555.230MANE Select
ENST00000261937.11EnsemblENSP00000261937.630MANE Select
NM_001354989.2RefSeqNP_001341918.130Standard
NM_002020.5RefSeqNP_002011.230Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
flt4Danio rerio

Structure: vascular lymphangioblast

Quality: absent

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)
  • Breast cancer - Homo sapiens (human)
  • Rap1 signaling pathway - Homo sapiens (human)
  • Ras signaling pathway - Homo sapiens (human)

Biological Process

  • positive regulation of protein phosphorylation
  • positive regulation of endothelial cell proliferation
  • vasculature development
  • lymph vessel development
  • lymphangiogenesis

Molecular Function

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

Cellular Component

  • extracellular region
  • nucleoplasm
  • plasma membrane
  • integral component of plasma membrane
  • receptor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000261937
Coding exons
30
Length
48119
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125748
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.836268600.7280.00005908853
Missense (PolyPhen)168328.310.51173481
Synonymous-1.774403951.110.00003102716
Loss of Function7.28571.40.07000.00000357764

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.0000560.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000440.000035rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr- 185', and of AKT1 at 'Ser-473'. {ECO:0000269|PubMed:11532940, ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:17210781, ECO:0000269|PubMed:19610651, ECO:0000269|PubMed:19779139, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:20445537, ECO:0000269|PubMed:21273538, ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872, ECO:0000269|PubMed:9435229}.;
Disease
DISEASE: Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269|PubMed:10835628, ECO:0000269|PubMed:10856194, ECO:0000269|PubMed:12881528, ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:16924388, ECO:0000269|PubMed:16965327, ECO:0000269|PubMed:17458866, ECO:0000269|PubMed:19289394, ECO:0000269|PubMed:26091405, ECO:0000269|PubMed:9817924}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.;

Recessive Scores

pRec
0.236

Intolerance Scores

LoFtool
0.0227
RVIS EVS
0.71
RVIS percentile EVS
85.53

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.766

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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