VCV000000432.123 - ClinVar

NM_000110.4(DPYD):c.1905+1G>A

Germline

Top reviewed classifications are shown here.

Submission summary:

25 submissions

21 submitters

10 conditions

Reviewed by expert panel

Drug response

May 2021 by PharmGKB

for capecitabine response - Toxicity

Drug response

May 2021 by PharmGKB

for fluorouracil response - Other

Drug response

May 2021 by PharmGKB

for fluorouracil response - Toxicity

Drug response

May 2021 by PharmGKB

for tegafur response - Toxicity

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000110.4(DPYD):c.1905+1G>A

Variation ID: 432 Accession: VCV000000432.123

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97450058 (GRCh38) [ NCBI UCSC ] 1: 97915614 (GRCh37) [ NCBI UCSC ] 1: 97688202 (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

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.1905+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000001.11:g.97450058C>T
NC_000001.10:g.97915614C>T
NC_000001.9:g.97688202C>T
NG_008807.2:g.476002G>A
LRG_722:g.476002G>A
LRG_722t1:c.1905+1G>A

... more HGVS ... less HGVS

Protein change

Other names

DPYD*2A
IVS14, G-A, +1

Canonical SPDI

NC_000001.11:97450057:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

exon loss; Variation Ontology [ VariO:0381] PubMed: 8892022

Global minor allele
frequency (GMAF)

The 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.

0.00300 (T)

Allele frequency

The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00265

Trans-Omics for Precision Medicine (TOPMed) 0.00280

1000 Genomes Project 0.00300

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00415

The Genome Aggregation Database (gnomAD) 0.00474

Links

Genetic Testing Registry (GTR): GTR000613316 Genetic Testing Registry (GTR): GTR000613417 OMIM: 612779.0001 dbSNP: rs3918290 PharmGKB Clinical Annotation: 827843617 ClinGen: CA114277 Genetic Testing Registry (GTR): GTR000528316 Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000613302 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 8892022 Fig. 3 to determine the location of this allele on the current reference sequence.

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
Gene	OMIM	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	413	547

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.
Dihydropyrimidine dehydrogenase deficiency	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000000460.30
Fluorouracil response	Pathogenic (2)	criteria provided, single submitter	May 4, 2016	RCV000030868.15
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000086468.42
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	no assertion criteria provided	Apr 1, 2015	RCV000201291.10
2-3 toe syndactyly Abnormal aggressive, impulsive or violent behavior Aggressive behavior Autism Bulbous nose Clinodactyly of the 5th toe Coarse facial features Cognitive impairment Frontal bossing Global developmental delay Hallux valgus Intellectual disability Intellectual disability, profound Macroglossia Mandibular prognathia Profound global developmental delay Seizure Short toe Shortening of all phalanges of fingers Slit-like opening of the exterior auditory meatus Thick lower lip vermilion Widely spaced teeth	Pathogenic (1)	criteria provided, single submitter	-	RCV000735355.10
fluorouracil response - Toxicity	drug response (1)	reviewed by expert panel	May 24, 2021	RCV001787337.10
fluorouracil response - Other	drug response (1)	reviewed by expert panel	May 24, 2021	RCV001787359.9
capecitabine response - Toxicity	drug response (1)	reviewed by expert panel	May 24, 2021	RCV001787360.10
tegafur response - Toxicity	drug response (1)	reviewed by expert panel	May 24, 2021	RCV001787361.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2021	RCV004018525.1

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 (Pharmacogenomics knowledge for personalized medicine) Method: curation	capecitabine response - Toxicity Drug used for Neoplasms Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031279.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (28) PubMed: 17000685‚ 17203168‚ 19104657‚ 19530960‚ 19795123‚ 20507294‚ 20819423‚ 21498394‚ 23585145‚ 23603345‚ 23736036‚ 23930673‚ 24167597‚ 24590654‚ 24647007‚ 24923815‚ 26603945‚ 27454530‚ 27738344‚ 27864592‚ 28481884‚ 28950804‚ 29065426‚ 29998006‚ 30114658‚ 30485432‚ 30723313‚ 31382864 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153760 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451274984 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. CYP2C93, HLA-B57:01) 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 (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Other Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031280.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Publications: PubMed (23) PubMed: 10071185‚ 10803677‚ 11895907‚ 11953843‚ 11988088‚ 16151913‚ 16361556‚ 17064846‚ 18600527‚ 20803296‚ 23328581‚ 25410891‚ 26216193‚ 26804652‚ 26967565‚ 28295243‚ 28929491‚ 31745289‚ 8698850‚ 9323575‚ 9439663‚ 9470816‚ 9472650 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153760 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451275020 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. CYP2C93, HLA-B57:01) 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 (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Toxicity Drug used for Neoplasms Affected status: yes Allele origin: germline	PharmGKB Accession: SCV000783062.2 First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (52): PubMed: 11156223 11350878 11555601 11953843 12209976 12360106 15017333 16361556 17064846 17121937 17165084 17335544 17700593 18299612 18443386 19104657 19473056 19530960 19795123 19858398 20385995 20803296 20809970 20819423 23481061 23585145 23603345 23736036 23930673 24167597 24700034 24817302 24923815 25381393 26099996 26603945 26794347 26846104 26967565 27738344 29065426 29134491 29998006 30114658 30485432 30723313 30775324 30898145 8698850 9439663 9470816 9472650 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153760 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/827843617 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. CYP2C93, HLA-B57:01) 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 (Pharmacogenomics knowledge for personalized medicine) Method: curation	tegafur response - Toxicity Drug used for Neoplasms Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031281.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (3) PubMed: 21410976‚ 23930673‚ 26603945 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153760 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451266065 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. CYP2C93, HLA-B57:01) 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)
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Dihydropyrimidine Dehydrogenase Deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359589.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (7) PubMed: 22339448‚ 10071185‚ 8698850‚ 8892022‚ 12360106‚ 17121937‚ 17335544 Comment: Across a selection of available literature, the c.1905+1G>A variant has been reported in at least 30 patients with dihydropyrimidine dehydrogenase deficiency, including in at least … (more) Across a selection of available literature, the c.1905+1G>A variant has been reported in at least 30 patients with dihydropyrimidine dehydrogenase deficiency, including in at least four patients in a homozygous state and in 26 patients in a heterozygous state, all of whom had 5-fluorouracil (5-FU) toxicity (Vreken et al. 1996; Van Kuilenburg et al. 1999; Van Kuilenburg et al. 2002; Morel et al. 2006; Magne et al. 2007). The c.1905+1G>A variant was found in one of 74 controls and is reported at a frequency of 0.02209 in the European (Finnish) population of the Exome Aggregation Consortium. The DPYD c.1905+1G>A variant occurs in a canonical splice site (donor) and results in skipping of exon 14 leading to an inactive DPYD allele (Wei et al. 1996). In patients with the c.1905+1G>A variant in a heterozygous state, conversion of 5-FU was shown to be 40% lower compared to controls (Van Kuilenburg et al. 2012). Based on the collective evidence, the c.1905+1G>A variant is classified as pathogenic for dihydropyrimidine dehydrogenase deficiency. (less)
Pathogenic (May 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	5-fluorouracil toxicity Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594401.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (May 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610939.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Jun 01, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225998.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 11895907‚ 23328581‚ 23335937 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DPYD Number of individuals with the variant: 14 Sex: mixed
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002028339.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: yes Allele origin: germline	3billion Accession: SCV002058930.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more) Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000432, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Clinodactyly of the 5th finger (present) , Global developmental delay (present) , Abnormal facial shape (present) , Failure to thrive (present) , Frontal bossing (present) … (more) Clinodactyly of the 5th finger (present) , Global developmental delay (present) , Abnormal facial shape (present) , Failure to thrive (present) , Frontal bossing (present) , Fetal growth restriction (present) , Intellectual disability, mild (present) , Fetal growth restriction (present) (less)
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002767928.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 8892022‚ 28929491 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 … (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 in this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with biallelic variants are well reported (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient cell-derived RNA demonstrates that this variant results in exon 14 skipping. This results in an inframe deletion, and the protein product p.(Asp581_Asn635del) (PMID: 8892022). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1590 heterozygotes, 9 homozygotes). (I) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in homozygous and compound heterozygous patients with dihydropyrimidine dehydrogenase deficiency (ClinVar, PMID: 8892022, PMID: 28929491). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient fibroblasts homozygous for this variant have been shown with no detectable enzyme activity (PMID: 8892022). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jul 31, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329338.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Individuals who carry at least one DPYD c.1905+1G>A 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 c.1905+1G>A 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 variant results in a nonfunctional DPYD protein (Offer et al., 2013); This variant is associated with the following publications: (PMID: 24700034, 19178088, 25525159, 11895907, 8892022, 12668826, 22975760, 25906475, 25087612, 22339448, 21114665, 15093568, 19473056, 26804652, 25590979, 26559152, 26603945, 30609409, 31124962, 30775324, 31980526, 33326653, 30755392, 32595208, 33877893, 23328581, 34426522, 34026625, 29152729, 34697415) (less)
Likely pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804714.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 09, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004859742.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 8892022‚ 11895907‚ 23328581‚ 25590979 Comment: The c.1905+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the DPYD gene. Alterations that disrupt the … (more) The c.1905+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the DPYD gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DPYD c.1905+1G>A alteration was observed in 0.57% (1608/282660) of total alleles studied including 9 homozygotes, with a frequency of 2.38% (599/25120) in the European (Finnish) subpopulation. This alteration (also referred to as DYPD*2A) has been reported in the homozygous and compound heterozygous states in patients with DPD deficiency and variable phenotypes including neurological disorders and 5-fluorouracil toxicity (Vreken, 1996; Johnson, 2002; Zhu, 2015). This nucleotide position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in exon 14 skipping, undetectable enzyme activity and inability to convert 5-FU to DHFU leading to 5-florouracil toxicity (Vreken, 1996; Johnson, 2002; Offer, 2013). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162929.3 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247769.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: DPYD: PM3:Strong, PP4:Moderate, PS3:Moderate, PVS1:Moderate, PM2:Supporting Number of individuals with the variant: 7
Pathogenic (Jan 18, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695411.1 First in ClinVar: Dec 31, 2017 Last updated: Dec 31, 2017	Publications: PubMed (4) PubMed: 11895907‚ 25590979‚ 8698850‚ 21919607
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	2-3 toe syndactyly Abnormal aggressive, impulsive or violent behavior Aggressive behavior Autism Bulbous nose Clinodactyly of the 5th toe Coarse facial features Cognitive impairment Frontal bossing Global developmental delay Hallux valgus Intellectual disability Intellectual disability, profound Macroglossia Mandibular prognathia Profound global developmental delay Seizure Short toe Shortening of all phalanges of fingers Slit-like opening of the exterior auditory meatus Thick lower lip vermilion Widely spaced teeth Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854509.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male
Pathogenic (Jul 09, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143792.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (68): PubMed: 23335937 23481061 23585145 23603345 24167597 24590654 24647007 24700034 24817302 8892022 28929491 28481884 26846104 26804652 26265035 26603945 26099996 25677447 25590979 25381393 23930673 23736036 23328581 21498394 11156223 9439663 7832988 29152729 8698850 9470816 10803677 11350878 11555601 11895907 11953843 12209976 12360106 15017333 15858133 16151913 17000685 17064846 17121937 17165084 17203168 17335544 17700593 18443386 18600527 19104657 19858398 20385995 24923815 25410891 26216193 26794347 26967565 27454530 27738344 27864592 28295243 29065426 24648345 10657402 21723269 12912951 30348537 11988088 Comment: The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency … (more) The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is more than 10 times the disease allele frequency. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families (less)
Pathogenic (Mar 24, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486085.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020609.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2017	Publications: PubMed (7) PubMed: 7832988‚ 8051923‚ 8698850‚ 8892022‚ 9470816‚ 9686374‚ 10071185 Comment on evidence: Meinsma et al. (1995) determined the molecular basis of dihydropyrimidine dehydrogenase deficiency (274270) by studying the phenotype and genotype of a family of a patient … (more) Meinsma et al. (1995) determined the molecular basis of dihydropyrimidine dehydrogenase deficiency (274270) by studying the phenotype and genotype of a family of a patient with no DPD activity. Fibroblast mRNAs from the patient and 4 family members were subjected to RT-PCR using primers generated from the human DPYD cDNA sequence. In the patient, DPYD mRNA was found to lack a segment of 165 nucleotides as a result of exon skipping. In the parents and 1 sib, DPYD mRNA was found to be heterozygous for the deletion, while a brother had only normal transcript. The deficient patient had no detectable DPD protein. The precise nature of the presumed splicing defect was not identified. The homozygous proband, who was first described by van Gennip et al. (1994), had been admitted to hospital at the age of 25 months with bilateral microphthalmia, coloboma of the iris and choroid, nystagmus, and a gradually increasing psychomotor retardation. No growth retardation or other neurologic abnormalities were detected. All other members of the pedigree were healthy and showed no ocular abnormalities. Wei et al. (1996) identified heterozygosity for the 165-nucleotide deletion in a British a cancer patient with partial DPD deficiency and severe toxicity after 5-fluorouracil treatment (see 274270). They found that a G-to-A transition within the 5-prime splice site of intron 14 resulted in exon skipping and an inactive DPYD allele. Independently, Vreken et al. (1996) showed that the 165-nucleotide deletion in the mature DPD mRNA was due to a G-to-A transition in the invariant GT dinucleotide splice donor site downstream of the skipped exon. The same mutation was identified in another, unrelated, Dutch patient. Because this mutation destroyed a unique MaeII restriction site, rapid screening was possible using restriction enzyme cleavage of the amplified genomic region encompassing this mutation. Analysis of 50 controls revealed no individuals heterozygous for the mutation. Although both patients had psychomotor retardation, the other features were different. The second patient presented with convulsions and had no ocular manifestations and no microcephaly. Van Kuilenburg et al. (1997) described another patient with severe 5-fluorouracil-related toxicity and heterozygosity for the same G-to-A splice site mutation with a deletion of 165 basepairs. Hyperpigmentation and cardiotoxicity were observed as side effects of 5-fluorouracil in this patient. The enzyme activity in leukocytes of the patient proved to be in the heterozygous range. The patients came from Denmark, Finland, and the Netherlands. The authors stated that the G-to-A mutation had been found in 8 of 11 patients with complete deficiency of the enzyme. Vreken et al. (1998) stated that the deletion of exon 14 due to the G-to-A mutation had been identified in 22 of 42 alleles from patients with complete DPD deficiency. Van Kuilenburg et al. (1999) found that the IVS14+1G-A mutation, leading to deletion of exon 14 of the DPYD gene, accounted for 23 of 44 (52%) DPD deficiency alleles. (less)
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	5-@FLUOROURACIL TOXICITY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020610.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2017	Publications: PubMed (7) PubMed: 7832988‚ 8051923‚ 8698850‚ 8892022‚ 9470816‚ 9686374‚ 10071185 Comment on evidence: Meinsma et al. (1995) determined the molecular basis of dihydropyrimidine dehydrogenase deficiency (274270) by studying the phenotype and genotype of a family of a patient … (more) Meinsma et al. (1995) determined the molecular basis of dihydropyrimidine dehydrogenase deficiency (274270) by studying the phenotype and genotype of a family of a patient with no DPD activity. Fibroblast mRNAs from the patient and 4 family members were subjected to RT-PCR using primers generated from the human DPYD cDNA sequence. In the patient, DPYD mRNA was found to lack a segment of 165 nucleotides as a result of exon skipping. In the parents and 1 sib, DPYD mRNA was found to be heterozygous for the deletion, while a brother had only normal transcript. The deficient patient had no detectable DPD protein. The precise nature of the presumed splicing defect was not identified. The homozygous proband, who was first described by van Gennip et al. (1994), had been admitted to hospital at the age of 25 months with bilateral microphthalmia, coloboma of the iris and choroid, nystagmus, and a gradually increasing psychomotor retardation. No growth retardation or other neurologic abnormalities were detected. All other members of the pedigree were healthy and showed no ocular abnormalities. Wei et al. (1996) identified heterozygosity for the 165-nucleotide deletion in a British a cancer patient with partial DPD deficiency and severe toxicity after 5-fluorouracil treatment (see 274270). They found that a G-to-A transition within the 5-prime splice site of intron 14 resulted in exon skipping and an inactive DPYD allele. Independently, Vreken et al. (1996) showed that the 165-nucleotide deletion in the mature DPD mRNA was due to a G-to-A transition in the invariant GT dinucleotide splice donor site downstream of the skipped exon. The same mutation was identified in another, unrelated, Dutch patient. Because this mutation destroyed a unique MaeII restriction site, rapid screening was possible using restriction enzyme cleavage of the amplified genomic region encompassing this mutation. Analysis of 50 controls revealed no individuals heterozygous for the mutation. Although both patients had psychomotor retardation, the other features were different. The second patient presented with convulsions and had no ocular manifestations and no microcephaly. Van Kuilenburg et al. (1997) described another patient with severe 5-fluorouracil-related toxicity and heterozygosity for the same G-to-A splice site mutation with a deletion of 165 basepairs. Hyperpigmentation and cardiotoxicity were observed as side effects of 5-fluorouracil in this patient. The enzyme activity in leukocytes of the patient proved to be in the heterozygous range. The patients came from Denmark, Finland, and the Netherlands. The authors stated that the G-to-A mutation had been found in 8 of 11 patients with complete deficiency of the enzyme. Vreken et al. (1998) stated that the deletion of exon 14 due to the G-to-A mutation had been identified in 22 of 42 alleles from patients with complete DPD deficiency. Van Kuilenburg et al. (1999) found that the IVS14+1G-A mutation, leading to deletion of exon 14 of the DPYD gene, accounted for 23 of 44 (52%) DPD deficiency alleles. (less)
Uncertain significance (Apr 01, 2015)	no assertion criteria provided Method: research	Hirschsprung disease 1 Affected status: yes Allele origin: germline	Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville. Accession: SCV000222717.1 First in ClinVar: Oct 29, 2015 Last updated: Oct 29, 2015
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Diasio Lab, Mayo Clinic Accession: SCV000118634.1 First in ClinVar: Feb 21, 2014 Last updated: Feb 21, 2014
not provided (-)	no classification provided Method: phenotyping only	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV004012817.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023	Comment: Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more) Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Abnormal circulating carnitine concentration (present) , Intellectual disability (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Autism (present) , … (more) Abnormal circulating carnitine concentration (present) , Intellectual disability (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Autism (present) , Seizure (present) , Male hypogonadism (present) , Short stature (present) , Infantile muscular hypotonia (present) , Abnormal cheek morphology (present) , Abnormal jaw morphology (present) , Wide mouth (present) , Widely spaced teeth (present) (less) Indication for testing: Diagnostic Age: 20-29 years Sex: male Method: Exome Sequencing Testing laboratory: PreventionGenetics, part of Exact Sciences Date variant was reported to submitter: 2020-01-14 Testing laboratory interpretation: Pathogenic
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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:

Across a selection of available literature, the c.1905+1G>A variant has been reported in at least 30 patients with dihydropyrimidine dehydrogenase deficiency, including in at least four patients in a homozygous state and in 26 patients in a heterozygous state, all of whom had 5-fluorouracil (5-FU) toxicity (Vreken et al. 1996; Van Kuilenburg et al. 1999; Van Kuilenburg et al. 2002; Morel et al. 2006; Magne et al. 2007). The c.1905+1G>A variant was found in one of 74 controls and is reported at a frequency of 0.02209 in the European (Finnish) population of the Exome Aggregation Consortium. The DPYD c.1905+1G>A variant occurs in a canonical splice site (donor) and results in skipping of exon 14 leading to an inactive DPYD allele (Wei et al. 1996). In patients with the c.1905+1G>A variant in a heterozygous state, conversion of 5-FU was shown to be 40% lower compared to controls (Van Kuilenburg et al. 2012). Based on the collective evidence, the c.1905+1G>A variant is classified as pathogenic for dihydropyrimidine dehydrogenase deficiency.

Comment:

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000432, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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 in this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with biallelic variants are well reported (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient cell-derived RNA demonstrates that this variant results in exon 14 skipping. This results in an inframe deletion, and the protein product p.(Asp581_Asn635del) (PMID: 8892022). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1590 heterozygotes, 9 homozygotes). (I) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in homozygous and compound heterozygous patients with dihydropyrimidine dehydrogenase deficiency (ClinVar, PMID: 8892022, PMID: 28929491). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient fibroblasts homozygous for this variant have been shown with no detectable enzyme activity (PMID: 8892022). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Individuals who carry at least one DPYD c.1905+1G>A 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 variant results in a nonfunctional DPYD protein (Offer et al., 2013); This variant is associated with the following publications: (PMID: 24700034, 19178088, 25525159, 11895907, 8892022, 12668826, 22975760, 25906475, 25087612, 22339448, 21114665, 15093568, 19473056, 26804652, 25590979, 26559152, 26603945, 30609409, 31124962, 30775324, 31980526, 33326653, 30755392, 32595208, 33877893, 23328581, 34426522, 34026625, 29152729, 34697415)

Comment:

The c.1905+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the DPYD gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DPYD c.1905+1G>A alteration was observed in 0.57% (1608/282660) of total alleles studied including 9 homozygotes, with a frequency of 2.38% (599/25120) in the European (Finnish) subpopulation. This alteration (also referred to as DYPD*2A) has been reported in the homozygous and compound heterozygous states in patients with DPD deficiency and variable phenotypes including neurological disorders and 5-fluorouracil toxicity (Vreken, 1996; Johnson, 2002; Zhu, 2015). This nucleotide position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in exon 14 skipping, undetectable enzyme activity and inability to convert 5-FU to DHFU leading to 5-florouracil toxicity (Vreken, 1996; Johnson, 2002; Offer, 2013). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is more than 10 times the disease allele frequency. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families

Comment:

Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Fluoropyrimidine-induced toxicity and DPD deficiency.. A case report of early onset, lethal capecitabine-induced toxicity and mini review of the literature. Uridine triacetate: Efficacy and safety as an antidote. Is it accessible outside USA?	Lampropoulou DI	Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners	2020	PMID: 31382864
Three different polymorphisms of the DPYD gene associated with severe toxicity following administration of 5-FU: a case report.	Mukherji D	Journal of medical case reports	2019	PMID: 30898145
DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A 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
Successful use of uridine triacetate (Vistogard) three weeks after capecitabine in a patient with homozygous dihydropyrimidine dehydrogenase mutation: A case report and review of the literature.	Zurayk M	Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners	2019	PMID: 28950804
Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity.	Fidai SS	Autopsy & case reports	2018	PMID: 30775324
DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.	Henricks LM	The Lancet. Oncology	2018	PMID: 30348537
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
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.	Amstutz U	Clinical pharmacology and therapeutics	2018	PMID: 29152729
DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.	Nahid NA	Cancer chemotherapy and pharmacology	2018	PMID: 29134491
Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency.	Henricks LM	International journal of cancer	2018	PMID: 28929491
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
Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity.	Nie Q	Clinical pharmacology and therapeutics	2017	PMID: 28295243
Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.	Roberto M	European journal of clinical pharmacology	2017	PMID: 27864592
Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer.	Borro M	Oncotarget	2017	PMID: 27738344
Highlight on DPYD gene polymorphisms and treatment by capecitabine (.).	Milano G	Scandinavian journal of clinical and laboratory investigation. Supplementum	2016	PMID: 27454530
Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort.	Mazzuca F	Oncotarget	2016	PMID: 26967565
DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia.	Zhao XQ	Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine	2016	PMID: 26846104
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
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
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.	Zhu X	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590979
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
The role of IVS14+1 G > A genotype detection in the dihydropyrimidine dehydrogenase gene and pharmacokinetic monitoring of 5-fluorouracil in the individualized adjustment of 5-fluorouracil for patients with local advanced and metastatic colorectal cancer: a preliminary report.	Cai X	European review for medical and pharmacological sciences	2014	PMID: 24817302
A rare cause of susceptibility to neutropenic sepsis in a patient with metastatic pancreas cancer.	Suarez Martinez-Falero B	BMJ case reports	2014	PMID: 24700034
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
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
Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule.	Magnani E	Internal and emergency medicine	2013	PMID: 23585145
Genetic variability & chemotoxicity of 5-fluorouracil & cisplatin in head & neck cancer patients: a preliminary study.	Dhawan D	The Indian journal of medical research	2013	PMID: 23481061
High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity.	Borràs E	Frontiers in genetics	2013	PMID: 23335937
Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity.	Offer SM	Cancer research	2013	PMID: 23328581
Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy.	van Kuilenburg AB	Clinical pharmacokinetics	2012	PMID: 22339448
Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.	Amstutz U	Pharmacogenomics	2011	PMID: 21919607
Genetic profiling of GSTP1, DPYD, FCGR2A, FCGR3A and CCND1 genes in an Argentinian population.	Galván CA	Clinical biochemistry	2011	PMID: 21723269
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
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
Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients.	Savva-Bordalo J	BMC cancer	2010	PMID: 20809970
Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity.	van Kuilenburg AB	Human genetics	2010	PMID: 20803296
Investigation of IVS14 + 1G > A polymorphism of DPYD gene in a group of Bosnian patients treated with 5-Fluorouracil and capecitabine.	Cerić T	Bosnian journal of basic medical sciences	2010	PMID: 20507294
Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.	Boige V	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2010	PMID: 20385995
The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients.	Loganayagam A	Cancer chemotherapy and pharmacology	2010	PMID: 19795123
Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial.	Braun MS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19858398
Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment.	Amstutz U	Pharmacogenomics	2009	PMID: 19530960
Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy.	Kleibl Z	Neoplasma	2009	PMID: 19473056
Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.	Gross E	PloS one	2008	PMID: 19104657
Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1G > A mutation in the dihydropyrimidine dehydrogenase gene.	van Kuilenburg AB	Nucleosides, nucleotides & nucleic acids	2008	PMID: 18600527
5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients.	Sulzyc-Bielicka V	Pharmacological reports : PR	2008	PMID: 18443386
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
Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity.	Magné N	British journal of clinical pharmacology	2007	PMID: 17335544
Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer.	Salgado J	Oncology reports	2007	PMID: 17203168
DPYD*2A mutation: the most common mutation associated with DPD deficiency.	Saif MW	Cancer chemotherapy and pharmacology	2007	PMID: 17165084
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
Pharmacogenetics of capecitabine in advanced breast cancer patients.	Largillier R	Clinical cancer research : an official journal of the American Association for Cancer Research	2006	PMID: 17000685
Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients.	Ezzeldin HH	Clinical cancer research : an official journal of the American Association for Cancer Research	2005	PMID: 16361556
Dihydropyrimidine dehydrogenase deficiency presenting at birth.	Al-Sanna'a NA	Journal of inherited metabolic disease	2005	PMID: 16151913
5-Fluorouracil/irinotecan induced lethal toxicity as a result of a combined pharmacogenetic syndrome: report of a case.	Steiner M	Journal of clinical pathology	2005	PMID: 15858133
Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients.	Salgueiro N	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15017333
Denaturing high performance liquid chromatography analysis of the DPYD gene in patients with lethal 5-fluorouracil toxicity.	Ezzeldin H	Clinical cancer research : an official journal of the American Association for Cancer Research	2003	PMID: 12912951
High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity.	Van Kuilenburg AB	Pharmacogenetics	2002	PMID: 12360106
Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation.	Van Kuilenburg AB	International journal of cancer	2002	PMID: 12209976
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
Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene.	Maring JG	British journal of cancer	2002	PMID: 11953843
Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype.	Johnson MR	Clinical cancer research : an official journal of the American Association for Cancer Research	2002	PMID: 11895907
Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls.	Raida M	Clinical cancer research : an official journal of the American Association for Cancer Research	2001	PMID: 11555601
Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency.	van Kuilenburg AB	Clinical cancer research : an official journal of the American Association for Cancer Research	2001	PMID: 11350878
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
Known variant DPYD alleles do not explain DPD deficiency in cancer patients.	Collie-Duguid ES	Pharmacogenetics	2000	PMID: 10803677
Common DPYD mutation associated with 5-fluorouracil toxicity detected by PCR-mediated site-directed mutagenesis.	Jézéquel P	Clinical chemistry	2000	PMID: 10657402
Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.	Van Kuilenburg AB	Human genetics	1999	PMID: 10071185
Dihydropyrimidine dehydrogenase deficiency: a novel mutation and expression of missense mutations in E. coli.	Vreken P	Journal of inherited metabolic disease	1998	PMID: 9686374
Dihydropyrimidine dehydrogenase pharmacogenetics in patients with colorectal cancer.	Ridge SA	British journal of cancer	1998	PMID: 9472650
Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity.	Van Kuilenburg AB	European journal of cancer (Oxford, England : 1990)	1997	PMID: 9470816
Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W.	Vreken P	Human genetics	1997	PMID: 9439663
Partial epilepsy in a girl with a symptom-free sister: first two Finnish patients with dihydropyrimidine dehydrogenase deficiency.	Holopainen I	Journal of inherited metabolic disease	1997	PMID: 9323575
A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency.	Vreken P	Journal of inherited metabolic disease	1996	PMID: 8892022
Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.	Wei X	The Journal of clinical investigation	1996	PMID: 8698850
Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea.	Meinsma R	DNA and cell biology	1995	PMID: 7832988
Clinical and biochemical findings in six patients with pyrimidine degradation defects.	van Gennip AH	Journal of inherited metabolic disease	1994	PMID: 8051923
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DPYD	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1451266065	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1451274984	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1451275020	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/827843617	-	-	-	-
https://www.pharmgkb.org/variant/PA166153760	-	-	-	-
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Text-mined citations for rs3918290 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000110.4(DPYD):c.1905+1G>A

Variant Details

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Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3918290 ...