FBN2 S2580L - GET-Evidence

Curation:
Currentness:

FBN2 S2580L

(FBN2 Ser2580Leu)


Short summary

Probably benign — initially associated with congenital contractual arachnodactyly, but later reports classify it as a nonpathogenic polymorphism.

Variant evidence
Computational
Functional -
Case/Control 3

High incidence in controls supports no significant pathogenic effect.

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

dominant

Summary of published research, and additional commentary

FBN2 is the only gene known to be associated with congenital contractural arachnodactyly. It remains to be seen whether mutations in FBN2 outside the “neonatal region” such as this variant cause phenotypes that are part of the spectrum of Marfan-like disease, but there is evidence that this variant is benign. Molecular genetic testing of the FBN2 gene encoding the extracellular matrix microfibril, fibrillin 2, is clinically available. Prenatal testing is available if the disease-causing mutation has been identified in an affected family member.

Total cases/controls case+ case– control+ control– p-value odds ratio
Congenital Contractural Arachnodactyly
0 49 3 37 0.0870 0.000

 

Allele frequency

  • A @ chr5:127609633: 7.8% (839/10758) in EVS
  • A @ chr5:127637531: 7.0% (9/128) in GET-Evidence
  • Frequency shown in summary reports: 7.8% (839/10758)

Publications
 

Park ES, Putnam EA, Chitayat D, Child A, Milewicz DM. Clustering of FBN2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development. Am J Med Genet. 1998 Jul 24;78(4):350-5. PubMed PMID: 9714438.

Pathogenic mutations of FBN2 cluster in exons 24 through 34, while mutations occuring in other exons, including some close to this variant, appear benign.

Robinson PN, Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet. 2000 Jan;37(1):9-25. Review. PubMed PMID: 10633129; PubMed Central PMCID: PMC1734449.

“It remains to be seen whether mutations in FBN2 outside the ‘neonatal region’ [exons 24 to 34, analogous to the neonatal regions of FBN1] cause phenotypes that are part of the spectrum of Marfan-like disease.”

Sakai H, Visser R, Ikegawa S, Ito E, Numabe H, Watanabe Y, Mikami H, Kondoh T, Kitoh H, Sugiyama R, Okamoto N, Ogata T, Fodde R, Mizuno S, Takamura K, Egashira M, Sasaki N, Watanabe S, Nishimaki S, Takada F, Nagai T, Okada Y, Aoka Y, Yasuda K, Iwasa M, Kogaki S, Harada N, Mizuguchi T, Matsumoto N. Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J Med Genet A. 2006 Aug 15;140(16):1719-25. PubMed PMID: 16835936.

3 out of 40 normal controls had this variant, classified as a polymorphism.

Cases/controls case+ case– control+ control– p-value odds ratio
Congenital Contractural Arachnodactyly
0 49 3 37 0.0870 0.000

 

Nishimura A, Sakai H, Ikegawa S, Kitoh H, Haga N, Ishikiriyama S, Nagai T, Takada F, Ohata T, Tanaka F, Kamasaki H, Saitsu H, Mizuguchi T, Matsumoto N. FBN2, FBN1, TGFBR1, and TGFBR2 analyses in congenital contractural arachnodactyly. Am J Med Genet A. 2007 Apr 1;143(7):694-8. PubMed PMID: 17345643.

This variant is reported as a harmless polymorphism because it is a registered SNP (rs2291628) in the hapmap database.

Genomes
 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr5:127609633

 

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr5:127609633

 

 

 

GS18517 - var-GS18517-1100-36-ASM
hom A @ chr5:127637532

 

GS18956 - var-GS18956-1100-36-ASM
het A @ chr5:127637532

 

GS19020 - var-GS19020-1100-36-ASM
het A @ chr5:127637532

 

GS19026 - var-GS19026-1100-36-ASM
het A @ chr5:127637532

 

GS19735 - var-GS19735-1100-36-ASM
het A @ chr5:127637532

 

Other external references
 

    dbSNP
  • rs2291628
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    Web search results (1 hit -- see all)

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in