rs3918290

This is a splice variant variant in the DPYD gene.

Key Literature Trait Associations

Fluoropyrimidine Toxicity

DPYD*2A (IVS14+1G>A) is a splice variant that causes exon 14 skipping and complete loss of dihydropyrimidine dehydrogenase (DPD) activity. Carriers face life-threatening toxicity from 5-fluorouracil and capecitabine, including severe neutropenia, mucositis, and potentially death. CPIC and EMA mandate pre-treatment DPYD testing: heterozygous carriers need 50% dose reduction, and homozygous carriers must avoid fluoropyrimidines entirely.

Amstutz U et al. “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.” Clinical Pharmacology and Therapeutics 103(2):210-216 (2018)

Allele T

OR —

p —

Candidate gene study

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GWAS Catalog Trait Associations (1)

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

uracil measurement

Yin X et al. “Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.” Nature Communications 13(1):1644 (2022)

Allele T

OR 1.43

p 6.0e-148

N 6,136

Large GWAS

European

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ClinVar annotation

Pathogenic★★★★

4 submitters100 publications

DPYD-related disorder; Dihydropyrimidine dehydrogenase deficiency (DPYDD); Fluorouracil response; Hirschsprung disease, susceptibility to, 1; Inborn genetic diseases; capecitabine response - Toxicity; fluorouracil response - Other; fluorouracil response - Toxicity; tegafur response - Toxicity

View on ClinVar →

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Research that mentions this SNP (2)

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DPYDGenotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer

AssociationN=1,545Valérie Boige et al.(2016)· JAMA Oncology

This pharmacogenetic secondary analysis of 1,545 stage III colon cancer patients from the PETACC-8 trial identified two DPYD variants significantly associated with grade 3+ fluorouracil-related adverse events: D949V (rs67376798, OR 6.3, p<0.001) and V732I/DPYD*6 (rs1801160, OR 1.7, p<0.001). The V732I association was validated in an independent cohort of 339 metastatic colorectal cancer patients treated with FOLFOX regimens.

Traits studied:DiarrheaFluorouracil-related adverse eventsGastrointestinal adverse eventsGrade 3+ hematologic adverse eventsMucositisNeutropenia

DOI Metascience Observatory

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Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency

Case reportN=22Van Kuilenburg AB et al.(1999)· Human Genetics

This review analyzes genotype and phenotype in 17 families with 22 patients having complete dihydropyrimidine dehydrogenase (DPD) deficiency. Seven mutations were identified: IVS14+1G>A (52% prevalence, splicing defect), 295-298delTCAT frameshift (16%), 1897delC frameshift (7%), and four missense mutations (C29R, R235W, R886H, V995F). Clinical phenotype is highly variable with convulsions, motor retardation, and mental retardation in ~45% of patients; no clear genotype-phenotype correlation was established.

Traits studied:Convulsive disordersDihydropyrimidine dehydrogenase deficiencyGrowth retardationMental retardationMicrocephalyMotor retardationOcular abnormalities