ClinVar Miner

Submissions for variant NM_000110.3(DPYD):c.2846A>T (p.Asp949Val) (rs67376798)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623094 SCV000741837 uncertain significance Inborn genetic diseases 2016-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Counsyl RCV000410600 SCV000486222 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-04-20 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America RCV000410600 SCV000695412 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2017-03-21 criteria provided, single submitter clinical testing Variant summary: The DPYD c.2846T>A (p.Asp949Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. The variant is located just outside of 4Fe-4S ferredoxin-type, iron-sulphur binding domain, but is predicted to have a negative effect on the domain formation due to the loss of the hydrogen bond between D949 and E951, resulting in decreased DPD activity (van Kuilenburg, 2002). This variant was found in 319/121374 control chromosomes of ExAC database at a frequency of 0.002628, including 1 homozygote, which exceeds the estimated maximal expected allele frequency of a pathogenic DPYD variant (0.0025). The variant has not, to our knowledge, been identified in DPD-deficient individuals that have neurological problems such as recurrent seizures (epilepsy), ID, microcephaly, hypertonia, delayed development of motor skills, indicating that heterozygous and homozygous individuals may be asymptomatic. However, the variant is cited as a polymorphism that is associated with a high risk for developing severe toxicity in cancer patients, including several fatal cases, following chemotherapy that included 5-fluorouracil and capecitabine (van Kuilenburg, 2000; Offer, 2014; Rosmarin, 2014). Therefore, reduction of fluoropyrimidine dosage in patients with p.Asp949Val is warranted by Clinical Pharmacogenetics Implementation Consortium as it may prevent severe and possibly life-threatening toxicities in patients who are homozygous for c.2846T>A or compound heterozygote with other drug-related alleles. The c.2846T>A is cited as likely pathogenic via ClinVar and PharmKB classifies the variant as moderate-to-strong (grade 3) drug-related toxicity. Taken together, the variant was classified as Likely Pathogenic to reflect inborn error of metabolism related to the dihydropyrimidine dehydrogenase deficiency based on the functional studies results.
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.

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