ClinVar Miner

Submissions for variant NM_000110.4(DPYD):c.2657G>A (p.Arg886His)

gnomAD frequency: 0.00003  dbSNP: rs1801267
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000000466 SCV000800648 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2018-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281683 SCV002571780 uncertain significance not specified 2022-08-05 criteria provided, single submitter clinical testing Variant summary: DPYD c.2657G>A (p.Arg886His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.2657G>A has been reported in the literature in at least one individual with Dihydropyrimidine Dehydrogenase Deficiency, who carried the variant of interest as well as C29R, both in the homozygous state (Vreken_1997, Van Kuilenburg_1999). The variant has also been cited in the literature in panels testing cancer patients for chemotherapy toxicity. These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. The variant was reported in an E. Coli based expression system to have 25% residual acitvity, and in a mammalian cell system to have activity similar to wild-type (Vreken_1997, Offer_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV000000466 SCV004049520 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000000466 SCV000020615 pathogenic Dihydropyrimidine dehydrogenase deficiency 1997-12-01 no assertion criteria provided literature only

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