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.
ClinVar Genomic variation as it relates to human health
NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)
Variation ID: 88974 Accession: VCV000088974.123
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p21.3 1: 97082391 (GRCh38) [ NCBI UCSC ] 1: 97547947 (GRCh37) [ NCBI UCSC ] 1: 97320535 (NCBI36) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 21, 2014 Oct 20, 2024 May 24, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000110.4:c.2846A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000101.2:p.Asp949Val missense NC_000001.11:g.97082391T>A NC_000001.10:g.97547947T>A NC_000001.9:g.97320535T>A NG_008807.2:g.843669A>T LRG_722:g.843669A>T LRG_722t1:c.2846A>T LRG_722p1:p.Asp949Val - Protein change
- D949V
- Other names
- -
- Canonical SPDI
- NC_000001.11:97082390:T:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00220 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00203
1000 Genomes Project 0.00220
Exome Aggregation Consortium (ExAC) 0.00263
The Genome Aggregation Database (gnomAD), exomes 0.00285
The Genome Aggregation Database (gnomAD) 0.00334
Trans-Omics for Precision Medicine (TOPMed) 0.00345
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00392
- Links
-
PharmGKB Clinical Annotation: 981203618 ClinGen: CA228077 Genetic Testing Registry (GTR): GTR000528316 Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000593450 Genetic Testing Registry (GTR): GTR000613302 Genetic Testing Registry (GTR): GTR000613316 Genetic Testing Registry (GTR): GTR000613417 dbSNP: rs67376798 VarSome
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DPYD | - | - |
GRCh38 GRCh37 |
414 | 548 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Aug 1, 2024 | RCV000086452.34 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 11, 2024 | RCV000410600.20 | |
| other (1) |
no assertion criteria provided
|
Feb 29, 2016 | RCV000500980.13 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
May 21, 2024 | RCV000623094.11 | |
|
capecitabine response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
May 24, 2021 | RCV001787864.10 |
|
tegafur response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
May 24, 2021 | RCV001787865.10 |
|
fluorouracil response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
May 24, 2021 | RCV001787336.10 |
|
fluorouracil response - Other
|
drug response (1) |
reviewed by expert panel
|
May 24, 2021 | RCV001787863.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
drug response
Drug-variant association: Toxicity
(May 24, 2021)
|
reviewed by expert panel
Method: curation
|
capecitabine response - Toxicity
Drug used for
Neoplasms
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV002031290.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
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 … (more)
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. (less)
|
|
|
drug response
Drug-variant association: Toxicity
(May 24, 2021)
|
reviewed by expert panel
Method: curation
|
fluorouracil response - Toxicity
Drug used for
Neoplasms
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000494717.3
First in ClinVar: Feb 19, 2017 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
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 … (more)
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. (less)
|
|
|
drug response
Drug-variant association: Toxicity
(May 24, 2021)
|
reviewed by expert panel
Method: curation
|
tegafur response - Toxicity
Drug used for
Neoplasms
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV002031292.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
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 … (more)
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. (less)
|
|
|
drug response
(May 24, 2021)
|
reviewed by expert panel
Method: curation
|
fluorouracil response - Other
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV002031291.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Apr 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidine dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486222.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidine dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695412.4
First in ClinVar: Jan 06, 2017 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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). The following publications have been ascertained in the context of this evaluation (PMID: 29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223). ClinVar contains an entry for this variant (Variation ID: 88974). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidine dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766693.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
|
|
|
Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidine dehydrogenase deficiency
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812380.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001147347.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
DPYD: PS3:Very Strong, PM2
Number of individuals with the variant: 9
|
|
|
other
(Feb 29, 2016)
|
no assertion criteria provided
Method: clinical testing
|
5-fluorouracil toxicity
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000594400.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Diasio Lab, Mayo Clinic
Accession: SCV000118618.1
First in ClinVar: Feb 21, 2014 Last updated: Feb 21, 2014 |
|
|
|
Benign
(Aug 20, 2020)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001804349.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
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 … (more)
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) (less)
|
|
|
Uncertain significance
(Nov 08, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741837.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Global developmental delay (present) , Developmental regression (present) , Attention deficit hyperactivity disorder (present) , Sleep disturbance (present) , Easy fatigability (present) … (more)
Seizures (present) , Global developmental delay (present) , Developmental regression (present) , Attention deficit hyperactivity disorder (present) , Sleep disturbance (present) , Easy fatigability (present) , Headache (present) , Incoordination (present) , Maternal teratogenic exposure (present) , Autistic disorder of childhood onset (present) , Encephalopathy (present) , EEG abnormality (present) , Cerebral atrophy (present) , Delayed speech and language development (present) , Syncope (present) , Premature birth (present) , Hypersomnia (present) , Tremor (present) , Intellectual disability (present) , Movement disorder (present) , Abnormality of immune system physiology (present) (less)
Sex: male
Ethnicity/Population group: Hispanic/Caucasian/Native American
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| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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). The following publications have been ascertained in the context of this evaluation (PMID: 29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223). ClinVar contains an entry for this variant (Variation ID: 88974). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
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
Comment:
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.
Comment:
DPYD: PS3:Very Strong, PM2
Comment:
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)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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). The following publications have been ascertained in the context of this evaluation (PMID: 29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223). ClinVar contains an entry for this variant (Variation ID: 88974). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
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
Comment:
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.
Comment:
DPYD: PS3:Very Strong, PM2
Comment:
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)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy. | Hamzic S | Swiss medical weekly | 2020 | PMID: 33232506 |
| A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency. | Pallet N | British journal of cancer | 2020 | PMID: 32595208 |
| Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. | Lunenburg CATC | European journal of human genetics : EJHG | 2020 | PMID: 31745289 |
| Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency. | Gbeto CC | Pharmacogenomics | 2019 | PMID: 31486738 |
| A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant. | De Falco V | Medicine | 2019 | PMID: 31124962 |
| The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study. | Iachetta F | British journal of cancer | 2019 | PMID: 30858516 |
| DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients. | Del Re M | The pharmacogenomics journal | 2019 | PMID: 30723313 |
| Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis. | Henricks LM | International journal of cancer | 2019 | PMID: 30485432 |
| Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time. | Coenen MJH | Current therapeutic research, clinical and experimental | 2018 | PMID: 30510603 |
| Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. | Madi A | European journal of cancer (Oxford, England : 1990) | 2018 | PMID: 30114658 |
| Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines. | Khushman M | Journal of gastrointestinal oncology | 2018 | PMID: 29998006 |
| Capecitabine Toxicity and Dihydropyrimidine Dehydrogenase Deficiency. | Tariq Z | American journal of therapeutics | 2018 | PMID: 29889674 |
| Preliminary Evidence for Enhanced Thymine Absorption: A Putative New Phenotype Associated With Fluoropyrimidine Toxicity in Cancer Patients. | Duley JA | Therapeutic drug monitoring | 2018 | PMID: 29846282 |
| Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. | Amstutz U | Clinical pharmacology and therapeutics | 2018 | PMID: 29152729 |
| Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. | Ruzzo A | British journal of cancer | 2017 | PMID: 29065426 |
| New advances in DPYD genotype and risk of severe toxicity under capecitabine. | Etienne-Grimaldi MC | PloS one | 2017 | PMID: 28481884 |
| Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. | Meulendijks D | British journal of cancer | 2017 | PMID: 28427087 |
| Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity. | Nie Q | Clinical pharmacology and therapeutics | 2017 | PMID: 28295243 |
| Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. | Meulendijks D | The pharmacogenomics journal | 2017 | PMID: 27995989 |
| 5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798). | González-Perera I | Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners | 2017 | PMID: 27122156 |
| Highlight on DPYD gene polymorphisms and treatment by capecitabine (.). | Milano G | Scandinavian journal of clinical and laboratory investigation. Supplementum | 2016 | PMID: 27454530 |
| Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene. | Kuilenburg ABPV | Biochimica et biophysica acta | 2016 | PMID: 26804652 |
| DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial. | Boige V | JAMA oncology | 2016 | PMID: 26794347 |
| Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio. | Thomas F | Clinical pharmacology and therapeutics | 2016 | PMID: 26265035 |
| Genotype-phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction. | Gentile G | The pharmacogenomics journal | 2016 | PMID: 26216193 |
| Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. | Meulendijks D | The Lancet. Oncology | 2015 | PMID: 26603945 |
| Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score. | Henricks LM | Pharmacogenomics | 2015 | PMID: 26265346 |
| Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines. | Toffoli G | International journal of cancer | 2015 | PMID: 26099996 |
| Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy. | Joerger M | Cancer chemotherapy and pharmacology | 2015 | PMID: 25677447 |
| Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity. | Froehlich TK | International journal of cancer | 2015 | PMID: 24923815 |
| A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. | Rosmarin D | Gut | 2015 | PMID: 24647007 |
| Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio. | Sistonen J | Pharmacogenomics | 2014 | PMID: 25410891 |
| DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). | Lee AM | Journal of the National Cancer Institute | 2014 | PMID: 25381393 |
| Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. | Offer SM | Cancer research | 2014 | PMID: 24648345 |
| Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. | Rosmarin D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2014 | PMID: 24590654 |
| Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. | Jennings BA | PloS one | 2013 | PMID: 24167597 |
| Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. | Caudle KE | Clinical pharmacology and therapeutics | 2013 | PMID: 23988873 |
| DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. | Terrazzino S | Pharmacogenomics | 2013 | PMID: 23930673 |
| Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. | Loganayagam A | British journal of cancer | 2013 | PMID: 23736036 |
| Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian and non-Caucasian patients with 5-FU- and capecitabine-related toxicity using full sequencing of DPYD. | Saif MW | Cancer genomics & proteomics | 2013 | PMID: 23603345 |
| A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity. | Offer SM | Clinical pharmacology and therapeutics | 2013 | PMID: 23588312 |
| Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. | Deenen MJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2011 | PMID: 21498394 |
| Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT) with leucovorin for locally advanced rectal cancer. | Cellier P | BMC cancer | 2011 | PMID: 21410976 |
| A bilateral cicatricial ectropion and bilateral upper lid shortening caused by 5-fluorouracil toxicity in a patient with dihydropyrimidine dehydrogenase deficiency. | Obi EE | Cutaneous and ocular toxicology | 2011 | PMID: 21077799 |
| Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients. | Kristensen MH | The Journal of international medical research | 2010 | PMID: 20819423 |
| The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients. | Loganayagam A | Cancer chemotherapy and pharmacology | 2010 | PMID: 19795123 |
| Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. | Gross E | PloS one | 2008 | PMID: 19104657 |
| Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. | Schwab M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18299612 |
| The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. | Capitain O | The pharmacogenomics journal | 2008 | PMID: 17700593 |
| 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. | Boisdron-Celle M | Cancer letters | 2007 | PMID: 17064846 |
| Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. | Morel A | Molecular cancer therapeutics | 2006 | PMID: 17121937 |
| Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. | Seck K | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16115930 |
| Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. | van Kuilenburg AB | The Biochemical journal | 2002 | PMID: 11988088 |
| Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. | van Kuilenburg AB | Clinical cancer research : an official journal of the American Association for Cancer Research | 2000 | PMID: 11156223 |
| https://www.pharmgkb.org/clinicalAnnotation/1451266120 | - | - | - | - |
| https://www.pharmgkb.org/clinicalAnnotation/1451274045 | - | - | - | - |
| https://www.pharmgkb.org/clinicalAnnotation/1451274090 | - | - | - | - |
| https://www.pharmgkb.org/clinicalAnnotation/981203618 | - | - | - | - |
| https://www.pharmgkb.org/variant/PA166153895 | - | - | - | - |
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Text-mined citations for rs67376798 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.