ClinVar Miner

Submissions for variant NM_000110.4(DPYD):c.2846A>T (p.Asp949Val) (rs67376798)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000417165 SCV000494716 drug response capecitabine response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000417132 SCV000494717 drug response fluorouracil response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000417148 SCV000494718 drug response Pyrimidine analogues response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000417175 SCV000494719 drug response tegafur response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Counsyl RCV000410600 SCV000486222 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410600 SCV000695412 pathogenic Dihydropyrimidine dehydrogenase deficiency 2021-06-04 criteria provided, single submitter clinical testing Variant summary: DPYD c.2846A>T (p.Asp949Val) results in a non-conservative amino acid change located in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (IPR017896) of 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 0.0028 in 251256 control chromosomes (gnomAD). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025). c.2846A>T has been reported in the literature in multiple individuals affected with Dihydropyrimidine Dehydrogenase Deficiency (e.g. van Kuilenburg_2002 and 2016, Henricks_2017, Pallet_2020). In addition, the variant was reported to be associated with lower DPD enzyme activity, reduced 5-fluorouracil clearances and increased risk of fluoropyrimidine-induced toxicity in heterozygous individuals (e.g. Caudle 2013, Henricks_2015, Madi 2018, Lunenburg_2020). Several Pharmacogenetics groups, including the Dutch Pharmacogenetics Working Group (DPWG), the Swiss Group of Pharmacogenomics and Personalised Therapy and the Clinical Pharmacogenetics Implementation Consortium (CPIC), recently released guidelines documenting c.2846A>T to be associated with moderately reduced DPD activity and strongly recommending DPYD genotyping of this and a few other variants prior to the start of therapy with fluoropyrimidines in cancer patients, followed by a reduction of the initial standard dose in genotyped-positive patients in order to decrease the risk of fluoropyrimidine-induced toxicity (Amstutz_2018, Hamzic_2020, Lunenburg_2020). Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased enzyme activity (e.g. van Kuilenburg_2002, Offer_2014, van Kuilenburg_2016, Henricks_2017). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), as likely pathogenic (n=1) and as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000623094 SCV000741837 uncertain significance Inborn genetic diseases 2016-11-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086452 SCV001147347 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410600 SCV001258887 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.
GeneDx RCV000086452 SCV001804349 benign not provided 2020-08-20 criteria provided, single submitter clinical testing Individuals who carry at least one DPYD D949V allele are at risk to experience drug toxicity when treated with fluoropyrimidine drugs. Dosing guidelines based on DPYD genotype are available (Amstutz et al., 2018); Published functional studies demonstrate decreased enzymatic activity for D949V (Kuilenburg et al., 2016; Offer et al., 2014); This variant is associated with the following publications: (PMID: 32595208, 31980526, 29152729, 10071185, 15377401, 17700593, 18299612, 19104657, 19296131, 19473056, 20819423, 21077799, 23736036, 23930673, 24167597, 24590654, 24648345, 25381393, 25410891, 24647007, 24923815, 25677447, 26099996, 26265346, 26216193, 27454530, 28295243, 28427087, 28481884, 29065426, 30114658, 21228398, 22995991, 31124962, 30609409, 11156223, 17064846, 17121937, 23988873, 26265035, 26804652, 16115930, 11875367, 27995989, 26794347, 30510603, 26603945, 23603345, 21498394, 21410976, 19795123, 11988088)
Diasio Lab, Mayo Clinic RCV000086452 SCV000118618 not provided not provided no assertion provided not provided
Genetic Services Laboratory, University of Chicago RCV000500980 SCV000594400 other Fluorouracil response 2016-02-29 no assertion criteria provided clinical testing

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