FLT4 N149D - GET-Evidence

Curation:
Currentness:

FLT4 N149D

(FLT4 Asn149Asp)


Short summary

Other severe variants in this gene are implicated in causing Milroy Disease (primary lymphedema) in a recessive manner. Although this variant is rare (2.3% allele frequency), it is still common enough that it is highly unlikely to have a severe, high penetrance pathogenic effect.

Variant evidence
Computational 1

Polyphen 2 reports an intermediate value “possibly damaging”. BLOSUM100 indicates this amino acid change is not generally disruptive.

Functional -
Case/Control 4

Incidence in controls contradicts pathogenic effect.

See unpublished research (below).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

GET-Evidence reports this variant as occurring in 3 out of 128 randomly selected genomes. Milroy disease is quite rare: GeneTests describes it as unknown prevalence but one of the more common causes of primary lymphedema (hereditary lymphedema). http://www.medscape.com/viewarticle/568789_2 describes incidence of primary lymphedema as occurring in 1.15 out of 100,000.

Taking a generous unknown variant hypothesis — that an unknown causal variant is responsible for causing primary lymphedema in 1 out of 200,000 individuals (half of all cases), and the variant has 50% penetrance — such a variant would be predicted to have an allele frequency of 0.224%. This variant observations (3 out of 128, 2.34%) is highly significantly divergent from such a hypothetical variant (p = 0.0031).

Allele frequency

  • C @ chr5:180057293: 7.3% (779/10744) in EVS
  • C @ chr5:179989898: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 7.3% (779/10744)

Publications
 

Iljin K, Karkkainen MJ, Lawrence EC, Kimak MA, Uutela M, Taipale J, Pajusola K, Alhonen L, Halmekytö M, Finegold DN, Ferrell RE, Alitalo K. VEGFR3 gene structure, regulatory region, and sequence polymorphisms. FASEB J. 2001 Apr;15(6):1028-36. PubMed PMID: 11292664.

Describes this variant as a polymorphism with 1% allele frequency.

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr5:180057293

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr5:180057293

 

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr5:180057293

 

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het C @ chr5:180057293

 

NA12878

 

Other external references
 

    dbSNP
  • rs34221241
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.358 (possibly damaging)
    Web search results (3 hits -- see all)
  • VEGFR3 gene structure, regulatory region, and sequence ...
    (N149D, T494A, P641S, and R1146H). The intra- genic polymorphic sites ... Alitalo, K. (1993) Two human FLT4 receptor tyrosine kinase. isoforms with distinct carboxy ...
    www.fasebj.org/cgi/reprint/15/6/1028.pdf
  • VEGFR3 gene structure, regulatory region, and sequence ...
    Key Words: FLT4 • receptor tyrosine kinase • promoter • endothelial cell ... amino acid substitutions in the coding sequence (N149D, T494A, P641S, and R1146H) ...
    www.fasebj.org/cgi/content/full/15/6/1028
  • VEGFR-3 in primary lymphedema
    FLT4. fms-like tyrosine kinase 4 (VEGFR-3) FOXC2. forkhead box C2. GDNF ... m s -like tyrosine kinase 4, FLT4) (Galland et al., 1993; Pajusola et ...
    ethesis.helsinki.fi/julkaisut/.../vk/karkkainen/vegfr3in.pdf

Other in silico analyses
 

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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