ClinVar Miner

Submissions for variant NM_000110.4(DPYD):c.187A>G (p.Lys63Glu)

gnomAD frequency: 0.00004  dbSNP: rs367619008
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669112 SCV000793825 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2017-11-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000669112 SCV001162934 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2024-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669112 SCV002103341 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2022-02-18 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV002531218 SCV003609723 uncertain significance Inborn genetic diseases 2022-06-21 criteria provided, single submitter clinical testing The c.187A>G (p.K63E) alteration is located in exon 3 (coding exon 3) of the DPYD gene. This alteration results from a A to G substitution at nucleotide position 187, causing the lysine (K) at amino acid position 63 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV004719931 SCV005324934 likely pathogenic not provided 2024-02-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on DPD activity (PMID: 29327356); 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: 34426522, 21420945, 36678742, 34959317, 19473056, 29327356)

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