NM_000311.5(PRNP):c.655G>A (p.Glu219Lys) AND Protection against Creutzfeldt-Jakob disease

Clinical significance:Uncertain significance (Last evaluated: Feb 1, 2012)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000014350.8

Allele description [Variation Report for NM_000311.5(PRNP):c.655G>A (p.Glu219Lys)]

NM_000311.5(PRNP):c.655G>A (p.Glu219Lys)

Gene:
PRNP:prion protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20p13
Genomic location:
Preferred name:
NM_000311.5(PRNP):c.655G>A (p.Glu219Lys)
HGVS:
  • NC_000020.11:g.4699875G>A
  • NG_009087.1:g.18725G>A
  • NM_000311.5:c.655G>AMANE SELECT
  • NM_001080121.3:c.655G>A
  • NM_001080122.3:c.655G>A
  • NM_001080123.3:c.655G>A
  • NM_001271561.3:c.*344G>A
  • NM_183079.4:c.655G>A
  • NP_000302.1:p.Glu219Lys
  • NP_001073590.1:p.Glu219Lys
  • NP_001073591.1:p.Glu219Lys
  • NP_001073592.1:p.Glu219Lys
  • NP_898902.1:p.Glu219Lys
  • NC_000020.10:g.4680521G>A
  • NM_000311.3:c.655G>A
  • P04156:p.Glu219Lys
Protein change:
E219K; GLU219LYS
Links:
UniProtKB: P04156#VAR_006477; OMIM: 176640.0019; dbSNP: rs1800014
NCBI 1000 Genomes Browser:
rs1800014
Molecular consequence:
  • NM_001271561.3:c.*344G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000311.5:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001080121.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001080122.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001080123.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_183079.4:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Protection against Creutzfeldt-Jakob disease
Identifiers:

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000034599OMIMno assertion criteria providedUncertain significance
(Feb 1, 2012)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Protective prion protein polymorphisms against sporadic Creutzfeldt-Jakob disease.

Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T.

Lancet. 1998 Feb 7;351(9100):419. No abstract available.

PubMed [citation]
PMID:
9482303

Prion susceptibility and protective alleles exhibit marked geographic differences.

Soldevila M, Calafell F, Andrés AM, Yagüe J, Helgason A, Stefánsson K, Bertranpetit J.

Hum Mutat. 2003 Jul;22(1):104-5.

PubMed [citation]
PMID:
12815603
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000034599.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)

Description

This variant, formerly titled CREUTZFELDT-JAKOB DISEASE, PROTECTION AGAINST, has been reclassified based on the findings of Beck et al. (2010) and Lukic et al. (2010).

Shibuya et al. (1998) reported a polymorphism of the PRNP gene in which there was a G-to-A transition in the first position of codon 219, resulting in a glu219-to-lys (E219K) substitution. In 20 definite and 65 probable Japanese cases of sporadic CJD (123400), the authors found that all individuals were 219glu homozygotes. Twelve of 100 persons from the general population were glu/lys heterozygotes and 88 were glu/glu homozygotes. Thus, the substitution of lys at codon 219 appeared to serve as a protective factor against sporadic CJD.

Shibuya et al. (1998) stated that the codon 219 glu/lys heterozygous polymorphism had not been detected in Europeans.

Soldevila et al. (2003) studied the codon 129 and E219K polymorphisms in 616 chromosomes from control individuals of all major continental groups. They found that the protective K219 allele was restricted to Asian and Pacific populations.

Nishida et al. (2004) stated that the frequency of the E219K allele in the Japanese population is 6%.

Nishida et al. (2004) reported a 68-year-old Japanese man with CJD who had a 72-bp insertion between codons 51 and 91 (176640.0001) and was homozygous for the 219K allele. The patient had relatively slow disease progression and no myoclonus, and the authors postulated that the E219K allele may have modified the phenotype in this patient. However, homozygosity for the allele was clearly not protective in this case.

Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM (176640.0005) and for 219QQ. The authors concluded that heterozygosity at either allele confers protection against the disease.

Lukic et al. (2010) reported 2 unrelated British patients with variant CJD who were heterozygous for the E219K allele. Both were homozygous for met129 (176640.0005). These findings suggested that the E219K variant is not protective against vCJD and may even confer increased risk. Tissue samples were only available from 1 patient and showed PrP(Sc) typical of vCJD; however, it was not known whether the PrP(Sc) was derived from the 219E allele or the 219K allele. Lukic et al. (2010) suggested that the 219K protein may not adopt the molecular conformations found in sporadic CJD, resulting in resistance to that disease, but that the 219K protein may permit pathogenic conversion when exposed to the bovine spongiform encephalopathy strain found in vCJD.

Beck et al. (2010) found E219K allele frequencies of approximately 0.1 up to 0.08 and 0.02 in Melanesian, Pakistani, and Bedouin populations, respectively. Although no association study could be performed, Beck et al. (2010) concluded that the variant is not pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 25, 2021

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