ClinVar Miner

Submissions for variant NM_000110.3(DPYD):c.703C>T (p.Arg235Trp) (rs1801266)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000362597 SCV000359606 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2017-04-27 criteria provided, single submitter clinical testing The DPYD c.703C>T (p.Arg235Trp) missense variant has been reported in one study in a compound heterozygous state with a frameshift variant in one individual with dihydropyrimidine dehydrogenase (DPD) deficieny (Vreken et al. 1997). The patient's mother was heterozygous for the p.Arg235Trp variant and had intermediate DPD activity, while the patient's father was homozygous for the frameshift variant and was completely DPD deficient (Vreken et al. 1997). Control data are unavailable for this variant, which is reported at a frequency of 0.0002 in the South Asian population of the Exome Aggregation Consortium. Expression of the p.Arg235Trp variant in E. coli showed DPD enzyme activity of approximately 1% that of the wild type enzyme. Crystal structure analysis of DPD indicated that the p.Arg235Trp variant interferes directly with cofactor and/or substrate binding (Dobritzsch et al., 2001). Offer et al. (2014) expressed the variant in an isogenic mammalian system and found a dramatic reduction in activity (12.5%–25%) compared to wild type. The evidence for this variant is limited. The p.Arg235Trp variant is classified as unknown significance, but suspicious for pathogenicity for dihydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
PharmGKB RCV000786703 SCV000925525 drug response fluorouracil response - Other reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.

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