WFS1 R611H - GET-Evidence

Curation:
Currentness:

WFS1 R611H

(WFS1 Arg611His)


Short summary

This nonsynonymous SNP is associated with Wolfram Syndrome (known as DIDMOAD), which is characterized by early-onset non-autoimmune diabetes mellitus, diabetes insipidus, optic atrophy, and deafness) and to adult Type Two Diabetes Mellitus. The WFS1 gene maps to chromosome 4p16.3. The variant has been shown to be statistically associated with type II diabetes in six UK studies and one study of Ashkenazi Jews (Sandhu, M., et al., Minton et al.).

Variant evidence
Computational 4

Variant Effect Predictor (Ensembl ):
missense mutation
SIFT=tolerated(0.41);
PolyPhen=probably_damaging(0.982);
Condel=deleterious(0.961)
Mutation Tasting Prediction: Polymorphism p value: 0.103212; no protein features affected.
SIFT: Affect protein function 0.00
GVGD: GV 0.00; GD 28.82; Class C25
Multi-alignment of O76024.2 wolframin [Homo sapiens] with: XP_003278562.1 [Nomascus leucogenys] NP_001127593.1 [Pongo abelii] XP_002746054.1 [Callithrix jacchus] XP_001092811.1 [Macaca mulatta] XP_002924196.1 [Ailuropoda melanoleuca] XP_001499848.1 [Equus caballus] BAE26190.1 [Mus musculus] NP_035846.1 [Mus musculus] AAH46988.1 [Mus musculus] AAC64944.1 [Mus musculus]

Functional 1

studies have been conducted for B-cell dysfunction

Case/Control 2

p=0.05 (Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in UK Populations- Minton et al.)

Familial -
 
Clinical importance
Severity 3

Type 2 Diabetes Mellitus can lead to nerve problems and kidney damage.

Treatability 4

Certain medications may be taken with insulin.

Penetrance 1

The OR was 1.24 (Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in UK Populations- Minton et al.).

 

Impact

Low clinical importance, Uncertain not reviewed

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03â��1.48], P = 0.02) (Franks, P.W., et al. – Replication of the Association Between Variants in the WFS1 gene and risk of Type 2 Diabetes in European Populations).
Minton, J. et al. (Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in UK Populations) studied the variant in patients from the U.K. with type II diabetes. Sandhu, M. et al. (Common Variants in WFS1 Confer Risk of Type 2 Diabetes) replicated the study in an Ashkenazi Jew population and in additional U.K. populations. Both found significant correlation between the variant and the phenotype.

Allele frequency

  • A @ chr4:6303354: 40.0% (4308/10758) in EVS
  • A @ chr4:6354254: 41.4% (48/116) in GET-Evidence
  • Frequency shown in summary reports: 40.0% (4308/10758)

Publications
 

Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R, Blech I, Pharoah PD, Palmer CN, Kimber C, Tavendale R, Morris AD, McCarthy MI, Walker M, Hitman G, Glaser B, Permutt MA, Hattersley AT, Wareham NJ, Barroso I. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007 Aug;39(8):951-3. Epub 2007 Jul 1. PubMed PMID: 17603484; PubMed Central PMCID: PMC2672152.

 

Di Lorenzo C, Sances G, Di Lorenzo G, Rengo C, Ghiotto N, Guaschino E, Perrotta A, Santorelli FM, Grieco GS, Troisi A, Siracusano A, Pierelli F, Nappi G, Casali C. The wolframin His611Arg polymorphism influences medication overuse headache. Neurosci Lett. 2007 Sep 13;424(3):179-84. Epub 2007 Aug 6. PubMed PMID: 17719176.

 

Cheng S, Wu Y, Wu W, Zhang D. Association of rs734312 and rs10010131 polymorphisms in WFS1 gene with type 2 diabetes mellitus: a meta-analysis. Endocr J. 2012 Dec 15. [Epub ahead of print] PubMed PMID: 23257691.

Since G allele encoding Arg® is associated with protective effect , this variant of H replacing R is annotated as the opposite, that is having association with risk of type II diabetes.

Genomes
 

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
hom A @ chr4:6303354

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr4:6303354

 

 

 

 

 

 

 

 

 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr4:6303354

 

 

 

 

 

 

 

 

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr4:6303354

 

 

 

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom A @ chr4:6303354

 

 

 

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr4:6303354

 

 

GS06985 - var-GS06985-1100-36-ASM
hom A @ chr4:6354255

 

GS06994 - var-GS06994-1100-36-ASM
het A @ chr4:6354255

 

GS07357 - var-GS07357-1100-36-ASM
hom A @ chr4:6354255

 

GS10851 - var-GS10851-1100-36-ASM
hom A @ chr4:6354255

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr4:6354255

 

GS18526 - var-GS18526-1100-36-ASM
hom A @ chr4:6354255

 

GS18537 - var-GS18537-1100-36-ASM
hom A @ chr4:6354255

 

GS18555 - var-GS18555-1100-36-ASM
het A @ chr4:6354255

 

GS18558 - var-GS18558-1100-36-ASM
hom A @ chr4:6354255

 

GS18940 - var-GS18940-1100-36-ASM
hom A @ chr4:6354255

 

GS18942 - var-GS18942-1100-36-ASM
het A @ chr4:6354255

 

GS18947 - var-GS18947-1100-36-ASM
hom A @ chr4:6354255

 

GS18956 - var-GS18956-1100-36-ASM
het A @ chr4:6354255

 

GS19648 - var-GS19648-1100-36-ASM
hom A @ chr4:6354255

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr4:6354255

 

GS19735 - var-GS19735-1100-36-ASM
het A @ chr4:6354255

 

GS19834 - var-GS19834-1100-36-ASM
het A @ chr4:6354255

 

GS20502 - var-GS20502-1100-36-ASM
het A @ chr4:6354255

 

Other external references
 

    dbSNP
  • rs734312
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the WFS1 gene
    Nonsyndromic Hearing Loss and Deafness, Autosomal Dominant
    DFNA 6/14/38 Nonsyndromic Hearing Loss and Deafness
    DFNA6/14/38 Nonsyndromic Low Frequency Sensorineural Hearing Los
    WFS1-Related Disorders
    Wolfram Syndrome
    Wolfram Syndrome-Like Disease
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/WFS1
    PolyPhen-2
  • Score: 0.99 (probably damaging)
    Web search results (15 hits -- see all)
  • Testing of diabetes-associated WFS1 polymorphisms in the ...
    WFS1, located on chromosome 4p16, encodes wolframin, a 100 kDa transmembrane ... WFS1 was included in a list of 84 candidate genes recently evaluated ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2483955
  • AceView: Gene:WFS1, a comprehensive annotation of human ...
    AceView offers a comprehensive annotation of human, mouse and nematode genes reconstructed by co-alignment and clustering of all publicly available mRNAs and ESTs on ...
    ncbi.nlm.nih.gov/IEB/Research/Acembly/...&a=clones&l=WFS1
  • Supplementary Table 2
    WFS1. R611H Positive> Positive. Exposed. No pattern. 588-610. transmembrane No signature. motif ... prediction. WFS1. G -> S Nonpolar> Nonpolar. Buried. No pattern. No domain ...
    www.mcponline.org/cgi/data/M500024-MCP200/DC1/2
  • Monogenic Diabetes in the Young, Pharmacogenetics and ...
    Genetic variation in WFS1 not only results in a rare syndrome characterized by early ... individuals, several SNPs in WFS1 (including a nonsynonymous SNP, R611H) were shown to ...
    edrv.endojournals.org/cgi/content/full/29/3/254?ck=nck
  • Supplementary Table 1:
    R611H. H. Minton, J. A. et al . Diabetes. 51,1287–1290 (2002) Disease associated synonymous ... WFS1. A684V. WFS1. E737K. WFS1. G576S. WFS1. G674R. WFS1. I333V. WFS1. I720V ...
    www.mcponline.org/cgi/data/M500024-MCP200/DC1/1
  • Type II- 95%
    ... PROT ID Variant site Phosphorylation site SWISS-PROT variant ID Removed kinase ... (dbSNP:rs1051338) 1718995 15489334 WFS1 O76024 R611H 614 VAR_005843 AGC (0.740) ...
    www.nih.go.kr/phosphovariant/html/group_whole/TypeII-_95.txt
  • Type II- 95%
    ... SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID ... 219 VAR_034880 JakA (0.607) Polymorphism (dbSNP:rs3816887) WFS1 O76024 E169K 170 ...
    nih.go.kr/phosphovariant/html/family_whole/TypeII-_95.txt
  • Polymorphisms in wolframin (WFS1) gene are possibly related ...
    Wolfram syndrome gene (WFS1) has been suggested to have a role in the ... R611H. Nonsynon ch. 0.53. 0.47. WFS1 2206 WFS1 24546. 8. rs # na. G. A. G736S ...
    www.biotech.ebc.ee/Publications/wolframinpaper.pdf
  • Common variants in WFS1 confer risk of type 2 diabetes
    Common variants in WFS1 confer risk of type 2 diabetes. Manjinder S Sandhu,1,2,14 Michael ... One nonsynonymous SNP (R611H, rs734312) is highly correlated with ...
    ukpmc.ac.uk/articlerender.cgi?accid=pmcA2672152

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

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