ClinVar Miner

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

gnomAD frequency: 0.00334  dbSNP: rs67376798
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787336 SCV000494717 drug response fluorouracil response - Toxicity 2021-05-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787864 SCV002031290 drug response capecitabine response - Toxicity 2021-05-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787863 SCV002031291 drug response fluorouracil response - Other 2021-05-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787865 SCV002031292 drug response tegafur response - Toxicity 2021-05-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
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 Center for Human Genetics Tuebingen RCV000086452 SCV001147347 pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing DPYD: PS3:Very Strong, PM2
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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000410600 SCV002766693 pathogenic Dihydropyrimidine dehydrogenase deficiency 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is known to be associated with autosomal recessive disease. However, heterozygous carriers of some variants may also show a reduction in dihydropyrimidine dehydrogenase activity and can present 5-fluorouracil toxicity (PMID: 29152729, 26265346). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 815 heterozygotes, 1 homozygote; v3: 493 heterozygotes, 3 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in an annotated domain or motif (4Fe-4S dicluster domain; NCBI). (I) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity (ClinVar, PMID: 11988088, 26804652, 30510603, 32595208). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces enzyme activity (PMID: 26804652, 24648345). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences RCV003915035 SCV004735894 likely benign DPYD-related disorder 2023-12-15 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Molecular Genetics, Royal Melbourne Hospital RCV000410600 SCV004812380 pathogenic Dihydropyrimidine dehydrogenase deficiency 2024-03-01 criteria provided, single submitter clinical testing This sequence change in DPYD is predicted to replace aspartic acid with valine at codon 949, p.(Asp949Val). The aspartic acid residue is highly conserved (100 vertebrates, Multiz alignments), and is located in the 4Fe-4S ferredoxin-type 2 domain. There is a large physicochemical difference between aspartic acid and valine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.6% (7,583/1,179,644 alleles, 29 homozygotes) in the European (non-Finnish) population. The variant is significantly associated with severe fluoropyrimidine-associated toxicity and is an annotated drug response allele with recommendations for fluoropyrimidine dosing (PMID: 26603945, 29152729, 24648345). It has been detected compound heterozygous with a second pathogenic variant in at least six individuals with dihydropyrimidine dehydrogenase (DPD) deficiency and/or severe fluoropyrimidine-related toxicity (PMID: 11988088, 17064846, 25381393, 26804652, 31124962, 32595208). Multiple individuals with this variant displayed loss/strongly decreased DPD enzyme activity and increased Uracil and Thymine plasma levels, which is highly specific for DPD deficiency (PMID: 11988088, 17064846, 26804652, 32595208). DPD enzyme activity assays in cell lines showed partially reduced activity indicating that this variant impacts protein function (PMID: 24648345, 26804652). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.962). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM3_Strong, PS3_Supporting, PP3_Moderate, PP4, BS1.
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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