PPOX P256R - GET-Evidence

Curation:
Currentness:

PPOX P256R

(PPOX Pro256Arg)


Short summary

This variant has 0.7% allele frequency in HapMap and occurs in a heme biosynthesis gene. Other variants in this gene are implicated in causing porphyria in a recessive manner, but this variant is considered a polymorphism and retains normal function in a eukaryotic expression system.

Variant evidence
Computational 1

Amino acid position not conserved.

See Whatley SD et al. 1999 (10486317).

Functional 1

Normal function in eukaryotic expression system.

See Kauppinen R et al. 2001 (11286631).

Case/Control 1

5% allele frequency in French population implies this is not significantly pathogenic.

See Whatley SD et al. 1999 (10486317).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

(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

 

Allele frequency

  • G @ chr1:161138933: 0.7% (78/10756) in EVS
  • Frequency shown in summary reports: 0.7% (78/10756)

Publications
 

Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, Elder GH, Deybach JC. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. 1999 Oct;65(4):984-94. PubMed PMID: 10486317; PubMed Central PMCID: PMC1288269.

This authors note that this variant is present in ~10% of the French population (allele frequency of 5%) and that this residue is poorly conserved between species.

Kauppinen R, Timonen K, von und zu Fraunberg M, Laitinen E, Ahola H, Tenhunen R, Taketani S, Mustajoki P. Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect. J Invest Dermatol. 2001 Apr;116(4):610-3. PubMed PMID: 11286631.

Reported a compound homozygote (together with I12T) in variegate porphyria. In eukarytotic cell lines this mutation shows normal activity, while I12T shows loss of enzyme function.

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 0.381 (possibly damaging)
    Web search results (10 hits -- see all)
  • Variegate Porphyria in Western Europe: Identification of PPOX ...
    Variegate Porphyria in Western Europe: Identification of PPOX Gene ... P256R mutation has previously been reported to be one. of two mutant PPOX alleles in a ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Mutation Screening of the Entire Coding Region of the ...
    ... activity of protoporphyrinogen oxidase (PPOX), the penultimate enzyme in the ... with mutations in the gene encoding PPOX and is usually inherited as an ...
    www.clinchem.org/cgi/content/full/47/6/1115
  • Homozygous variegate porphyria: 20 y follow-up and ...
    Department of Medicine, Division of Diabetology, Dermatology and Clinical ... (I12T) and a 767C to G transversion in exon 7 (P256R) of the protoporphyrinogen ...
    www.ncbi.nlm.nih.gov/pubmed/11286631
  • 1115
    PPOX by substitution of the nucleotide positioned in. IVS7–9 has been reported, which ... Variegate porphyria in Western Europe: identification of PPOX gene muta ...
    www.clinchem.org/cgi/reprint/47/6/1115.pdf
  • Type III 97%
    ... SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID ... Reference(s) for variant Reference(s) for phosphorylation site TPSD1 Q9BZJ3 P15R ...
    nih.go.kr/phosphovariant/html/family_whole/TypeIII_97.txt
  • OMIM: 600923
    The authors concluded that mild PPOX mutations occur in the general population ... P256R mutation resulted in less than half of normal PPOX activity in the ...
    www.genome.jp/htbin/www_bget?omim+600923
  • Homozygous variegate porphyria: 20 y follow-up and ...
    The long-term follow-up of a homozygous variegate porphyria patient revealed severe photosensitivity accompanied by mild sensory neuropathy and IgA nephropathy.
    www.medscape.com/medline/abstract/11286631

Other in silico analyses
 

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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