ClinVar Miner

Submissions for variant NM_000110.3(DPYD):c.775A>G (p.Lys259Glu) (rs45589337)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224513 SCV000281065 likely benign not provided 2016-04-21 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
PreventionGenetics,PreventionGenetics RCV000249889 SCV000302306 benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000249889 SCV000700574 benign not specified 2016-11-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000249889 SCV000917305 likely benign not specified 2018-07-24 criteria provided, single submitter clinical testing Variant summary: DPYD c.775A>G (p.Lys259Glu) results in a conservative amino acid change located in the FAD/NAD(P)-binding domain 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 0.006 in 245824 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is benign. The variant, c.775A>G, has been reported in individuals affected with 5-FU-related toxicity (Gross_2003, Harismendy_2013, Schwab_2008). One of these studies also described that the DPYD enzyme activity measured from the cytosolic fraction of a patients PBM cells (who was heterozygous for the variant) was in the normal range (Gross_2003). These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. A publication, Offer_2014, functionally assessed the variant and found the variant to cause normal enzyme activity in an in vitro expression system. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000986378 SCV001135368 benign Dihydropyrimidine dehydrogenase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986378 SCV001259747 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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