ClinVar

Description

Variant summary: DPYD c.187A>G (p.Lys63Glu) results in a conservative amino acid change located in the Dihydroprymidine dehydrogenase domain II (IPR028261) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250872 control chromosomes. c.187A>G has been reported in the literature as a compound heterozygous genotype with this variant and the classical DPYD*2A allele in at-least one individual affected with classical features of autosomal recessive Dihydropyrimidine Dehydrogenase Deficiency (example, Weidensee_2011) and has also been reported in individuals experiencing high toxicity to fluoropyramidines (example, Kleibl_2009). At least one publication reports experimental evidence evaluating an impact on protein function (example, Shreshta_2018). The most pronounced variant effect results in <10% of normal in-vitro DPYD activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.