PRNP M129V - GET-Evidence

Curation:
Currentness:

PRNP M129V

(PRNP Met129Val)


Short summary

This variant is associated with some protective effects for prion disease — individuals homozygous for this variant are less susceptible to Creutzfeldt-Jakob, and Papua New Guinea individuals heterozygotes at this site are less susceptible to kuru.

Variant evidence
Computational 3

PolyPhen: Possibly damaging 0.583
SIFT: Affect protein function 0.01
GVGD: GV 0.00; GD 20.52; Class C15
Variant Effect Predictor (Ensembl ):
SIFT=deleterious(0.01);
PolyPhen=benign(0.019);
Condel=deleterious(0.900)
Mutation Tasting Prediction: Polymorphism, P value: 0. 768693; protein features (might be) affected (aa 23-230 REGION Interaction with GRB2, ERI3 and SYN1 (By similarity) gets lost)

Functional -
Case/Control 5

High significance evidence

See Mead S et al. 2009 (19081515).

Familial -
 
Clinical importance
Severity 4
Treatability 1
Penetrance

Prion diseases are extremely rare

 

Impact

Low clinical importance, protective

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

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr20:4680251: 34.0% (3653/10758) in EVS
  • G @ chr20:4628250: 24.2% (31/128) in GET-Evidence
  • Frequency shown in summary reports: 34.0% (3653/10758)

Publications
 

Shibao C, Garland EM, Gamboa A, Vnencak-Jones CL, Van Woeltz M, Haines JL, Yu C, Biaggioni I. PRNP M129V homozygosity in multiple system atrophy vs. Parkinson's disease. Clin Auton Res. 2008 Feb;18(1):13-9. Epub 2008 Jan 30. PubMed PMID: 18236005.

Found no correlation between codon 129 and MSA.

Mead S, Poulter M, Uphill J, Beck J, Whitfield J, Webb TE, Campbell T, Adamson G, Deriziotis P, Tabrizi SJ, Hummerich H, Verzilli C, Alpers MP, Whittaker JC, Collinge J. Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study. Lancet Neurol. 2009 Jan;8(1):57-66. PubMed PMID: 19081515; PubMed Central PMCID: PMC2643048.

Homozygosity for this variant was associated with a significant protective effect for Creutzfeldt-Jakob (p = 2.7e-4 in replication group). Heterozygous version (and not homozygous) of this variant was also found to be protective against kuru by, it is theorized, extending incubation time (2.2e-9). In general, this GWAS study “confirms the strong association of PRNP codon 129 (rs1799990) across acquired and sporadic prion diseases as the outstanding genetic risk factor in human prion disease”.

Genomes
 

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het G @ chr20:4680251

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het G @ chr20:4680251

 

 

 

 

 

 

 

 

 

 

 

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het G @ chr20:4680251

 

 

 

 

 

 

 

 

 

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het G @ chr20:4680251

 

 

 

GS06994 - var-GS06994-1100-36-ASM
hom G @ chr20:4628251

 

GS07357 - var-GS07357-1100-36-ASM
het G @ chr20:4628251

 

GS10851 - var-GS10851-1100-36-ASM
hom G @ chr20:4628251

 

GS18501 - var-GS18501-1100-36-ASM
het G @ chr20:4628251

 

GS18504 - var-GS18504-1100-36-ASM
het G @ chr20:4628251

 

GS18505 - var-GS18505-1100-36-ASM
het G @ chr20:4628251

 

GS18517 - var-GS18517-1100-36-ASM
het G @ chr20:4628251

 

GS18537 - var-GS18537-1100-36-ASM
het G @ chr20:4628251

 

GS19025 - var-GS19025-1100-36-ASM
het G @ chr20:4628251

 

GS19026 - var-GS19026-1100-36-ASM
het G @ chr20:4628251

 

GS19648 - var-GS19648-1100-36-ASM
het G @ chr20:4628251

 

GS19670 - var-GS19670-1100-36-ASM
het G @ chr20:4628251

 

GS19701 - var-GS19701-1100-36-ASM
het G @ chr20:4628251

 

GS19703 - var-GS19703-1100-36-ASM
het G @ chr20:4628251

 

GS19704 - var-GS19704-1100-36-ASM
het G @ chr20:4628251

 

GS20502 - var-GS20502-1100-36-ASM
hom G @ chr20:4628251

 

Other external references
 

    dbSNP
  • rs1799990
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the PRNP gene
    Familial Creutzfeldt-Jakob Disease
    Fatal Familial Insomnia
    Genetic Prion Diseases
    Gerstmann-Straussler-Scheinker Disease
    Huntington Disease-Like 1
    5-Oxoprolinuria
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PRNP
    GWAS
  • Creutzfeldt-Jakob disease (rs1799990-A)
    Mead 11-Dec-08 in Lancet Neurol
    OR or beta: NR NR
    p-value: 2.00E-21
    Initial sample: 117 CJD cases, 3,083 controls
    Replication sample: 506 sCJD cases, 28 iCJD cases, 151 Kuru cases, 125 Kuru-resistant cases, up to 1,137 controls
    www.ncbi.nlm.nih.gov/pubmed/19081515
    PharmGKB
  • [Creutzfeldt-Jakob Syndrome]
    GWAS results: Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study. (Initial Sample Size: 117 CJD cases, 3,083 controls; Replication Sample Size: 506 sCJD cases, 28 iCJD cases, 151 Kuru cases, 125 Kuru-resistant cases, up to 1,137 controls); (Region: 20p13; Reported Gene(s): PRNP; Risk Allele: rs1799990-A); (p-value= 2E-21).This variant is associated with Creutzfeldt-Jakob disease.
    www.ncbi.nlm.nih.gov/pubmed/19081515; Web Resource:http://www.genome.gov/gwastudie
    PolyPhen-2
  • Score: 0.628 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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