DPYD R29C - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

DPYD R29C

(DPYD Arg29Cys)


Short summary

This variant is also known as DPYD*9A, and is associated with Dihydropyrimidine dehydrogenase deficiency and impaired clearance of 5-fluorouracil with potential toxic consequence.

Variant evidence
Computational 1

NBLOSUM=5, this gene is associated with this disease, position not conserved.
PolyPhen2: Benign, score 0.072
SIFT: Affect protein function 0.01
GVGD: GV 28.82; GD 169.74; Class C45
Variant Effect Predictor (Ensembl):
SIFT=tolerated(0.18);
PolyPhen=benign(0.072);
Condel=neutral(0.447)
Mutation Tasting Prediction: Polymorphism, P value: 0.580684; protein features (might be) affected.

See Vreken P et al. 1997 (9439663), unpublished research (below).

Functional 1

E. coli

See Vreken P et al. 1997 (9439663).

Case/Control -
Familial -
 
Clinical importance
Severity 5

Potentially lethal in homozygous and toxic in heterozygous individuals.

See Vreken P et al. 1997 (9439663), Zhang H et al. 2007 (17848752).

Treatability 4

Use alternate chemotherapy protocol or lower dosage to compensate for lower drug clearance.

See Zhang H et al. 2007 (17848752).

Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr1:98348885: 71.4% (7680/10758) in EVS
  • A @ chr1:98121472: 71.9% (92/128) in GET-Evidence
  • Frequency shown in summary reports: 71.4% (7680/10758)

Publications
 

Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet. 1997 Dec;101(3):333-8. PubMed PMID: 9439663.

This variant was identified in three individuals with Dihydropyrimidine dehydrogenase (DPD) deficiency as part of two different compound heterozygotes (with either IVS14 (del(exon14)) or R886H). In a functional assay this variant alone was sufficient to abolish expression of function enzyme in E. coli. This position is not conserved. They note the potential lethal effect of 5-fluoruracil on homozygous individuals and toxic effect on heterozygous individuals.

McLeod HL, Collie-Duguid ES, Vreken P, Johnson MR, Wei X, Sapone A, Diasio RB, Fernandez-Salguero P, van Kuilenberg AB, van Gennip AH, Gonzalez FJ. Nomenclature for human DPYD alleles. Pharmacogenetics. 1998 Dec;8(6):455-9. PubMed PMID: 9918128.

This variant is named DPYD*9A

Collie-Duguid ES, Etienne MC, Milano G, McLeod HL. Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics. 2000 Apr;10(3):217-23. PubMed PMID: 10803677.

In a study of 37 individuals for variants associated with DPD deficiency, it was noted that these variants (including our variant) do not sufficiently explains enzyme levels and two individuals with normal enzyme levels were found to be homozygous for this variant.

van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA, Maring JG, Vreken P, van Gennip AH. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000 Dec;6(12):4705-12. PubMed PMID: 11156223.

The authors report evidence contrary to that of Collie-Duguid et al., and find that C29R mutations do contribute to 5FU toxicity.

Zhang H, Li YM, Zhang H, Jin X. DPYD*5 gene mutation contributes to the reduced DPYD enzyme activity and chemotherapeutic toxicity of 5-FU: results from genotyping study on 75 gastric carcinoma and colon carcinoma patients. Med Oncol. 2007;24(2):251-8. PubMed PMID: 17848752.

An analysis of 75 individuals undergoing chemotherapy with 5FU found that the 7 individuals heterozygous for this variant had significantly increased incidence of middle-severe nausea and vomiting than the wildtype.

Genomes
 

 

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
hom A @ chr1:98348885

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom A @ chr1:98348885

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr1:98348885

 

 

 

 

 

 

 

 

 

 

 

 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr1:98348885

 

 

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
hom A @ chr1:98348885

 

 

 

 

 

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom A @ chr1:98348885

 

 

 

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom A @ chr1:98348885

 

 

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom A @ chr1:98348885

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
hom A @ chr1:98348885

 

 

 

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
hom A @ chr1:98348885

 

 

 

GS06985 - var-GS06985-1100-36-ASM
hom A @ chr1:98121473

 

GS06994 - var-GS06994-1100-36-ASM
hom A @ chr1:98121473

 

GS07357 - var-GS07357-1100-36-ASM
het A @ chr1:98121473

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr1:98121473

 

GS12004 - var-GS12004-1100-36-ASM
hom A @ chr1:98121473

 

GS18501 - var-GS18501-1100-36-ASM
het A @ chr1:98121473

 

GS18502 - var-GS18502-1100-36-ASM
het A @ chr1:98121473

 

GS18504 - var-GS18504-1100-36-ASM
hom A @ chr1:98121473

 

GS18508 - var-GS18508-1100-36-ASM
hom A @ chr1:98121473

 

GS18517 - var-GS18517-1100-36-ASM
hom A @ chr1:98121473

 

GS18526 - var-GS18526-1100-36-ASM
hom A @ chr1:98121473

 

GS18537 - var-GS18537-1100-36-ASM
hom A @ chr1:98121473

 

GS18555 - var-GS18555-1100-36-ASM
hom A @ chr1:98121473

 

GS18558 - var-GS18558-1100-36-ASM
hom A @ chr1:98121473

 

GS18940 - var-GS18940-1100-36-ASM
hom A @ chr1:98121473

 

GS18942 - var-GS18942-1100-36-ASM
hom A @ chr1:98121473

 

GS18947 - var-GS18947-1100-36-ASM
hom A @ chr1:98121473

 

GS18956 - var-GS18956-1100-36-ASM
hom A @ chr1:98121473

 

GS19017 - var-GS19017-1100-36-ASM
het A @ chr1:98121473

 

GS19020 - var-GS19020-1100-36-ASM
het A @ chr1:98121473

 

GS19025 - var-GS19025-1100-36-ASM
hom A @ chr1:98121473

 

GS19129 - var-GS19129-1100-36-ASM
het A @ chr1:98121473

 

GS19239 - var-GS19239-1100-36-ASM
het A @ chr1:98121473

 

GS19648 - var-GS19648-1100-36-ASM
hom A @ chr1:98121473

 

GS19649 - var-GS19649-1100-36-ASM
hom A @ chr1:98121473

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr1:98121473

 

GS19670 - var-GS19670-1100-36-ASM
hom A @ chr1:98121473

 

GS19704 - var-GS19704-1100-36-ASM
hom A @ chr1:98121473

 

GS19735 - var-GS19735-1100-36-ASM
hom A @ chr1:98121473

 

GS19834 - var-GS19834-1100-36-ASM
het A @ chr1:98121473

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr1:98121473

 

GS21767 - var-GS21767-1100-36-ASM
het A @ chr1:98121473

 

Other external references
 

    dbSNP
  • rs1801265
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    Web search results (21 hits -- see all)
  • Pharma DMET - SNPedia
    ... del DPYD DPYD_>(V335L) DPYD*11_(V335L) noncore snp DPYD DPYD_1679T>G(I560S) DPYD ... DPYD DPYD_37594C>T(R29C) DPYD_37594C>T(R29C) core snp rs1801265 DPYD ...
    www.snpedia.com/index.php/Pharma_DMET

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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