IL7R T244I - GET-Evidence

Curation:
Currentness:

IL7R T244I

(IL7R Thr244Ile)


Short summary

The reference genome variant for this allele has been associated with a slight increased risk of multiple sclerosis. Thus, this variant can be treated as a “protective” variant — carriers of this variant are slightly less likely to have MS. Because the disease is rare and the effect of this variant is not very strong, the absolute decreased risk for carriers of this variant is less than .05% (less than 1 in 2000).

Variant evidence
Computational -1

Other IL7R variants are associated with multiple sclerosis. Computational methods predict this variant is benign/tolerated.
PolyPhen: Benign, score 0.000
SIFT: Tolerated 0.29
GVGD: GV 89.28; GD 0.00; Class C0 Variant Effect Predictor (Ensembl ):
SIFT=tolerated(0.43);
PolyPhen=benign(0);
Condel=deleterious(0.562)
Mutation Tasting Prediction: Polymorphism, P value: 0.146466; protein features (might be) affected (aa 240-264 TRANSMEM Helical (potential) gets lost)

Functional 1

The T244I variation is located in an important transmembrane domain of IL7R.

Case/Control 5

See Gregory SG et al. 2007 (17660817).

Familial

No familial data

 
Clinical importance
Severity 4
Treatability 3
Penetrance
 

Impact

Low clinical importance, Likely protective

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

Inheritance pattern

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Summary of published research, and additional commentary

The interleukin-7 receptor alpha-chain gene (IL7R) codes for the receptor for IL-7, which is an important T-cell growth factor in T- and B-cell expansion. There is an association between the IL7R T244I polymorphism and multiple sclerosis. The T244I variation is located in an important transmembrane domain of IL7R.

The “T” variant is the non-reference genotype and leads to the T244I amino acid variant. The “C” variant is reported to cause increased risk of MS — this is the reference genotype at this location and corresponds to the reference amino acid “244T”. Thus, T244I is slightly protective.

Because MS is quite rare with the high-end incidence estimate of .15%, the 1.3 odds ratio translates to less than .05% absolute increased risk for homozygous carriers of this variant.

Allele frequency

  • T @ chr5:35874575: 21.0% (2261/10758) in EVS
  • T @ chr5:35910331: 18.8% (24/128) in GET-Evidence
  • Frequency shown in summary reports: 21.0% (2261/10758)

Publications
 

Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur J Hum Genet. 2003 Jul;11(7):509-15. PubMed PMID: 12825072.

 

International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007 Aug 30;357(9):851-62. Epub 2007 Jul 29. PubMed PMID: 17660530.

 

Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet. 2007 Sep;39(9):1108-13. Epub 2007 Jul 29. PubMed PMID: 17660816.

 

Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL; Multiple Sclerosis Genetics Group. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007 Sep;39(9):1083-91. Epub 2007 Jul 29. PubMed PMID: 17660817.

Reports CC individuals (homozygous reference) have 1.29 odds ratio for MS w/ p-value of 0.00008.

Zhang R, Duan L, Jiang Y, Zhang X, Sun P, Li J, Zhang M, Tang G, Wang X, Li X. Association between the IL7R T244I polymorphism and multiple sclerosis: a meta-analysis. Mol Biol Rep. 2010 Dec 16. [Epub ahead of print] PubMed PMID: 21161391.

 

Genomes
 

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr5:35874575

 

 

 

 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr5:35874575

 

 

 

 

 

 

 

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het T @ chr5:35874575

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het T @ chr5:35874575

 

 

GS06985 - var-GS06985-1100-36-ASM
het T @ chr5:35910332

 

GS06994 - var-GS06994-1100-36-ASM
het T @ chr5:35910332

 

GS12004 - var-GS12004-1100-36-ASM
het T @ chr5:35910332

 

GS18555 - var-GS18555-1100-36-ASM
het T @ chr5:35910332

 

GS18947 - var-GS18947-1100-36-ASM
het T @ chr5:35910332

 

GS19649 - var-GS19649-1100-36-ASM
hom T @ chr5:35910332

 

GS19669 - var-GS19669-1100-36-ASM
het T @ chr5:35910332

 

GS19670 - var-GS19670-1100-36-ASM
het T @ chr5:35910332

 

GS19700 - var-GS19700-1100-36-ASM
het T @ chr5:35910332

 

Other external references
 

    dbSNP
  • rs6897932
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Multiple sclerosis (rs6897932-C)
    De Jager 14-Jun-09 in Nat Genet
    OR or beta: 1.12 [1.02-1.23]
    Risk allele frequency: 0.75
    p-value: 0.000002
    Initial sample: 2,624 cases, 7,220 controls
    Replication sample: 2,215 cases, 2,116 controls
    www.ncbi.nlm.nih.gov/pubmed/19525953
  • Multiple sclerosis (rs6897932-C)
    Hafler 29-Jul-07 in N Engl J Med
    OR or beta: 1.18 [1.11-1.26]
    Risk allele frequency: 0.75
    p-value: 3.00E-07
    Initial sample: 931 trios, 2,431 controls
    Replication sample: 609 trios, 2,322 cases, 2,987 controls
    www.ncbi.nlm.nih.gov/pubmed/17660530
  • Type 1 diabetes (rs6897932-G)
    Todd 6-Jun-07 in Nat Genet
    OR or beta: 1.12 [1.06-1.19]
    Risk allele frequency: 0.71
    p-value: 8E-06
    Initial sample: 1,963 cases, 2,938 controls
    Replication sample: 2997 trios, 4,000 cases, 5,000 controls
    www.ncbi.nlm.nih.gov/pubmed/17554260
    PharmGKB
  • [Multiple Sclerosis]
    This nonsynonymous coding SNP in exon 6 of IL7R showed highly significant evidence of association with multiple sclerosis.
    www.ncbi.nlm.nih.gov/pubmed/17660530
  • [Multiple Sclerosis]
    In a case-control study of Nordic populations, rs6897932 was the most strongly associated of several SNPs associated with risk of multiple sclerosis.
    www.ncbi.nlm.nih.gov/pubmed/17660816
  • [Multiple Sclerosis]
    GWAS Results: Risk alleles for multiple sclerosis identified by a genomewide study (Initial Sample Size: 931 trios, 2,431 controls; Replication Sample Size: 609 trios, 2,322 cases, 2,987 controls; Risk Allele: rs6897932-C).
    www.ncbi.nlm.nih.gov/pubmed/17660530; Web Resource:http://www.genome.gov/gwastudie
    Web search results (29 hits -- see all)
  • Rs6897932 - SNPedia
    [PMID 19626041] Variation in IL7R predisposes to sarcoid inflammation ... IL7R: T244I. Annotation. This nonsynonymous coding SNP in exon 6 of IL7R showed highly ...
    www.snpedia.com/index.php?title=Rs6897932
  • Interleukin 7 receptor a chain (IL7R) shows allelic and ...
    IL7R does not extend to any flanking genes, indicating that the only ... rs6897932 (T244I) in exon 6 of IL7R is strongly associated with. increased multiple ...
    direct-ms.org/pdf/.../IL 7 gene Nature Genetics 07.pdf
  • Genes and Immunity - Abstract of article: Variation in IL7R ...
    Genes and Immunity is a journal dedicated to functional genetics of the immune response. ... variation in IL7R may confer general risk for developing granulomatous lung disease. ...
    www.nature.com/gene/journal/v10/n7/abs/gene200955a.html
  • Heron, M (M)
    Heron, M (M) :: Racial inequality in active life among adult Americans. [Excretion of ... was to investigate the role of the IL7R gene region in susceptibility to sarcoidosis. ...
    lib.bioinfo.pl/auid:263148
  • Table 2 : Robust associations of four new chromosome regions ...
    Nature Genetics publishes the very highest quality research in genetics. It encompasses ... rs1445898 and IL7R SNPs rs3194051 and rs6897932, respectively. IL7R is also called ...
    www.nature.com/ng/journal/v39/n7/fig_tab/ng2068_T2.html
  • Interleukin 7 receptor alpha chain (IL7R) shows allelic and ...
    BioInfoBank Library :: Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. The role of the CD58 locus in ...
    lib.bioinfo.pl/pmid:17660817
  • METHODS AND COMPOSITIONS FOR CORRELATING GENETIC MARKERS WITH ...
    ... exon 6, soluble IL7Rα chain and membrane bound IL7Rα chain as described herein. ... an IL7Rα mRNA lacking exon 6, thereby producing a soluble form of the IL7Rα chain protein. ...
    www.faqs.org/patents/app/20090035778
  • NEJM -- Risk Alleles for Multiple Sclerosis Identified by a ...
    Original Article from The New England Journal of Medicine -- Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study
    content.nejm.org/cgi/content/full/NEJMoa073493v1?ck=nck
  • new england journal
    encoding IL2Rα and IL7Rα are associated with. multiple sclerosis ... change (T244I) that alters the ratio of soluble to. membrane-bound interleukin-7 receptor ...
    content.nejm.org/cgi/reprint/357/9/851.pdf
  • available
    We developed this resource to help us analyze the progress made so far toward ... it for all to use in the hope that it will help others in their search for the ...
    www.acceleratedcure.org/downloads/phase2-genetic-studies.xls

Other in silico analyses
 

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

Edit history
 

Gene search

"GENE" or "GENE A123C":

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