ClinVar Miner

Submissions for variant NM_000110.4(DPYD):c.2378C>T (p.Thr793Ile)

gnomAD frequency: 0.00002  dbSNP: rs547099198
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674813 SCV000800214 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2018-05-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553732 SCV001774716 uncertain significance not specified 2021-07-22 criteria provided, single submitter clinical testing Variant summary: DPYD c.2378C>T (p.Thr793Ile) results in a non-conservative amino acid change located in the Dihydroorotate dehydrogenase domain (IPR005720) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250994 control chromosomes. c.2378C>T has been reported in the literature as a heterozygous genotype among at-least one healthy volunteer of East African descent (example, Elraiyah_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in-vitro and the authors note that this may contribute towards sensitivity to 5-fluorouracil in the East African population (example, Elraiyah_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genome-Nilou Lab RCV000674813 SCV004049525 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2023-04-11 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV004691273 SCV005186782 uncertain significance not provided criteria provided, single submitter not provided
GeneDx RCV004691273 SCV005326248 uncertain significance not provided 2023-06-13 criteria provided, single submitter clinical testing Identified in a cohort of healthy individuals of East African background undergoing screening for DPYD variants with increased risk of adverse reactions to fluoropyrimidine drugs (Elraiyah et al., 2017); Published functional studies demonstrate a damaging effect with reduction of DPYD function (Elraiyah et al, 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32707991, 27727460)

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