rs1799990

badMag 7.5

This is a variant in the PRNP gene that changes a methionine to an valine.

Key Literature Trait Associations

Variant CJD (BSE-Related) Susceptibility

All definite clinical cases of variant CJD (linked to BSE exposure) have been Met/Met homozygous at codon 129. In a study of 128 vCJD cases in the UK, 100% were Met/Met, compared to ~37% of the general population. Heterozygosity (Met/Val) appears to confer strong resistance to vCJD, likely representing one of the strongest known examples of heterozygote advantage in humans.

Mead S et al. “Genetic susceptibility, evolution and the kuru epidemic” The Lancet. Neurology (2009)
Allele A
OR —
p —
Candidate gene study
Diack AB et al. “Variant CJD. 18 years of research and surveillance.” Prion (2014)
Allele A
OR —
p —
N 32,441
Preliminary work
European
Bishop MT et al. “PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism.” Bmc Medical Genetics (2009)
Allele A
OR —
p —
N 1,445
Preliminary work
European

Sporadic Creutzfeldt-Jakob Disease Susceptibility

The Met/Met (A;A) genotype at PRNP codon 129 is significantly overrepresented in sporadic CJD cases compared to controls. In a meta-analysis of 4,653 sCJD cases and 7,297 controls, Met homozygosity conferred an OR of ~1.71 for sCJD risk relative to heterozygotes. The Met/Val heterozygous state is strongly protective against all forms of prion disease.

Jones E et al. “Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.” The Lancet. Neurology 19(10):840-848 (2020)
Allele A
OR 1.23
p 2.7e-15
N 17,679
Large GWAS
European
Mead S et al. “Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.” Human Molecular Genetics 21(8):1897-1906 (2012)
Allele A
OR 1.71
p 1.0e-15
Meta-analysis
Bishop MT et al. “PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism.” Bmc Medical Genetics (2009)
Allele A
OR —
p —
N 1,445
Preliminary work
European

Sporadic CJD clinical duration

rs1799990 (PRNP codon 129 Met/Val) is the dominant genome-wide modifier of clinical duration in sporadic CJD. In a GWAS of 3,773 sCJD cases with clinical duration data (Hummerich et al. 2024), the A allele showed p=3.45×10⁻³⁶ (beta=0.34) under an additive model, and p=9.92×10⁻⁶⁷ (beta=0.84) under a heterozygous model, indicating that Met/Val heterozygotes survive significantly longer than Met/Met homozygotes. No other common variant approached genome-wide significance for this phenotype, illustrating remarkable genetic parsimony in prion disease course modification.

Hummerich H et al. “Genome wide association study of clinical duration and age at onset of sporadic CJD.” Plos One (2024)
Allele A
OR —
β 0.340
p 3.5e-36
N 3,773
Large GWAS
European
▶

GWAS Catalog Trait Associations (2)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

Creutzfeldt Jacob Disease

Mead S et al. “Genetic susceptibility, evolution and the kuru epidemic” The Lancet. Neurology (2009)
Allele A
OR —
p 2.0e-21
N 3,200
Large GWAS
multi-ancestry
▶

ClinVar annotation

Pathogenic★★★☆
18 submitters48 publications

Autism spectrum disorder; Fatal familial insomnia (FFI); Gerstmann-Straussler-Scheinker syndrome (GSD); Huntington disease-like 1 (HDL1); Inherited Creutzfeldt-Jakob disease; Inherited prion disease; Kuru, susceptibility to; Spongiform encephalopathy with neuropsychiatric features; not specified

View on ClinVar →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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