VCV000000435.9 - ClinVar

NM_000110.4(DPYD):c.85T>C (p.Cys29Arg)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

5 submitters

5 conditions

Reviewed by expert panel

Drug response

Mar 2021 by PharmGKB

for capecitabine response - Toxicity

Drug response

Mar 2021 by PharmGKB

for fluorouracil response - Toxicity

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000110.4(DPYD):c.85T>C (p.Cys29Arg)

Variation ID: 435 Accession: VCV000000435.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97883329 (GRCh38) [ NCBI UCSC ] 1: 98348885 (GRCh37) [ 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	Dec 26, 2017	Feb 20, 2024	Mar 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.85T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000101.2:p.Cys29Arg	missense
NM_001160301.1:c.85T>C	NP_001153773.1:p.Cys29Arg	missense
NC_000001.11:g.97883329A>G
NC_000001.10:g.98348885=
NG_008807.2:g.42731T>C
LRG_722:g.42731T>C
LRG_722t1:c.85T>C	LRG_722p1:p.Cys29Arg
LRG_722t2:c.85T>C	LRG_722p2:p.Cys29Arg
	Q12882:p.Cys29Arg

... more HGVS ... less HGVS

Protein change

C29R

Other names

Canonical SPDI

NC_000001.11:97883328:A:G

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

Global minor allele frequency (GMAF) Help 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.26468

Trans-Omics for Precision Medicine (TOPMed) 0.27344

The Genome Aggregation Database (gnomAD) 0.27966

Links

ClinGen: CA114278 UniProtKB: Q12882#VAR_005173 OMIM: 612779.0004 dbSNP: rs1801265 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
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 (1)	no assertion criteria provided	Dec 1, 1997	RCV000000464.11
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 20, 2023	RCV000711510.15
fluorouracil response - Toxicity	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV001787363.10
capecitabine response - Toxicity	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV001787362.10
not specified	Benign (1)	criteria provided, single submitter	May 4, 2022	RCV002247229.9

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 (Mar 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: SCV002031275.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (11) PubMed: 19530960‚ 20819423‚ 21498394‚ 24590654‚ 24647007‚ 24923815‚ 25677447‚ 28481884‚ 29065426‚ 29998006‚ 30114658 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153648 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451287240 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 (Mar 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: SCV002031276.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (17) PubMed: 11156223‚ 14635116‚ 17121937‚ 17848752‚ 18299612‚ 19473056‚ 19530960‚ 20819423‚ 23481061‚ 24434920‚ 24923815‚ 26794347‚ 26846104‚ 27752409‚ 29065426‚ 29998006‚ 30114658 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153648 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/981201981 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)
Benign (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518454.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Benign (Nov 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001092616.4 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Nov 20, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841886.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018
Pathogenic (Dec 01, 1997)	no assertion criteria provided Method: literature only	DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020613.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017	Publications: PubMed (2) PubMed: 9266349‚ 9439663 Comment on evidence: Vreken et al. (1997) described 2 patients with DPD deficiency (274270) who were compound heterozygous for 2 mutations in the DPYD gene: a cys29-to-arg (C29R) … (more) Vreken et al. (1997) described 2 patients with DPD deficiency (274270) who were compound heterozygous for 2 mutations in the DPYD gene: a cys29-to-arg (C29R) substitution and the common donor splice site mutation (612779.0001). Only one of these patients showed a convulsive disorder during childhood, whereas the other showed no clinical phenotype, further illustrating the lack of correlation between genotype and phenotype in DPD deficiency. Vreken et al. (1997) described another patient who was compound heterozygous for C29R and an R886H substitution (612779.0006) in the DPYD gene. The patient had been hospitalized for upper airway infection and was being investigated for unexplained hypokalemia. However, there were no convulsions or other neurologic abnormalities. By assaying recombinant C29R mutant enzyme, they found that C29R had no detectable DPYD activity; however, R886H showed activity about 40% of normal. The authors concluded that the C29R mutation alone was sufficient to explain the DPD-deficient phenotype and that the R886H mutation was probably a rare polymorphism. (less)

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:

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
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
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
The First Case of Severe Takotsubo Cardiomyopathy Associated with 5-Fluorouracil in a Patient with Abnormalities of Both Dihydropyrimidine Dehydrogenase (DPYD) and Thymidylate Synthase (TYMS) Genes.	Saif MW	Cureus	2016	PMID: 27752409
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
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
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
Dihydropyrimidine dehydrogenase 85T>C mutation is associated with ocular toxicity of 5-fluorouracil: a case report.	Baskin Y	American journal of therapeutics	2015	PMID: 24434920
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
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
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
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
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
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
DPYD*5 gene mutation contributes to the reduced DPYD enzyme activity and chemotherapeutic toxicity of 5-FU: results from genotyping study on 75 gastric carcinoma and colon carcinoma patients.	Zhang H	Medical oncology (Northwood, London, England)	2007	PMID: 17848752
Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance.	Morel A	Molecular cancer therapeutics	2006	PMID: 17121937
Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects.	Gross E	Human mutation	2003	PMID: 14635116
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
Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W.	Vreken P	Human genetics	1997	PMID: 9439663
Identification of novel point mutations in the dihydropyrimidine dehydrogenase gene.	Vreken P	Journal of inherited metabolic disease	1997	PMID: 9266349
https://www.pharmgkb.org/clinicalAnnotation/1451287240	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/981201981	-	-	-	-
https://www.pharmgkb.org/variant/PA166153648	-	-	-	-
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Text-mined citations for rs1801265 ...

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.85T>C (p.Cys29Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801265 ...