VCV000298300.10 - ClinVar

NM_000110.4(DPYD):c.703C>T (p.Arg235Trp)

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

2 conditions

Reviewed by expert panel

Drug response

Mar 2021 by PharmGKB

for fluorouracil response - Other

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000110.4(DPYD):c.703C>T (p.Arg235Trp)

Variation ID: 298300 Accession: VCV000298300.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97691776 (GRCh38) [ NCBI UCSC ] 1: 98157332 (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 6, 2016	Jun 17, 2024	Mar 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.703C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000101.2:p.Arg235Trp	missense
NC_000001.11:g.97691776G>A
NC_000001.10:g.98157332G>A
NG_008807.2:g.234284C>T
LRG_722:g.234284C>T
LRG_722t1:c.703C>T	LRG_722p1:p.Arg235Trp
	Q12882:p.Arg235Trp

... more HGVS ... less HGVS

Protein change

R235W

Other names

Canonical SPDI

NC_000001.11:97691775:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00008

Exome Aggregation Consortium (ExAC) 0.00010

Links

ClinGen: CA963582 Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000613417 UniProtKB: Q12882#VAR_005174 dbSNP: rs1801266 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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 13, 2024	RCV000362597.9
fluorouracil response - Other	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV000786703.3

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 (Mar 24, 2021)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Other Affected status: yes Allele origin: germline	PharmGKB Accession: SCV000925525.2 First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021	Publications: PubMed (3) PubMed: 10071185‚ 24648345‚ 9439663 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153649 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1447989706 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)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359606.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (3) PubMed: 24648345‚ 9439663‚ 11179210 Comment: The DPYD c.703C>T (p.Arg235Trp) missense variant has been reported in one study in a compound heterozygous state with a frameshift variant in one individual with … (more) The DPYD c.703C>T (p.Arg235Trp) missense variant has been reported in one study in a compound heterozygous state with a frameshift variant in one individual with dihydropyrimidine dehydrogenase (DPD) deficieny (Vreken et al. 1997). The patient's mother was heterozygous for the p.Arg235Trp variant and had intermediate DPD activity, while the patient's father was homozygous for the frameshift variant and was completely DPD deficient (Vreken et al. 1997). Control data are unavailable for this variant, which is reported at a frequency of 0.0002 in the South Asian population of the Exome Aggregation Consortium. Expression of the p.Arg235Trp variant in E. coli showed DPD enzyme activity of approximately 1% that of the wild type enzyme. Crystal structure analysis of DPD indicated that the p.Arg235Trp variant interferes directly with cofactor and/or substrate binding (Dobritzsch et al., 2001). Offer et al. (2014) expressed the variant in an isogenic mammalian system and found a dramatic reduction in activity (12.5%â€“25%) compared to wild type. The evidence for this variant is limited. The p.Arg235Trp variant is classified as unknown significance, but suspicious for pathogenicity for dihydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Mar 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194069.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

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:

The DPYD c.703C>T (p.Arg235Trp) missense variant has been reported in one study in a compound heterozygous state with a frameshift variant in one individual with dihydropyrimidine dehydrogenase (DPD) deficieny (Vreken et al. 1997). The patient's mother was heterozygous for the p.Arg235Trp variant and had intermediate DPD activity, while the patient's father was homozygous for the frameshift variant and was completely DPD deficient (Vreken et al. 1997). Control data are unavailable for this variant, which is reported at a frequency of 0.0002 in the South Asian population of the Exome Aggregation Consortium. Expression of the p.Arg235Trp variant in E. coli showed DPD enzyme activity of approximately 1% that of the wild type enzyme. Crystal structure analysis of DPD indicated that the p.Arg235Trp variant interferes directly with cofactor and/or substrate binding (Dobritzsch et al., 2001). Offer et al. (2014) expressed the variant in an isogenic mammalian system and found a dramatic reduction in activity (12.5%â€“25%) compared to wild type. The evidence for this variant is limited. The p.Arg235Trp variant is classified as unknown significance, but suspicious for pathogenicity for dihydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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
Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity.	Offer SM	Cancer research	2014	PMID: 24648345
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.	Dobritzsch D	The EMBO journal	2001	PMID: 11179210
Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.	Van Kuilenburg AB	Human genetics	1999	PMID: 10071185
Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W.	Vreken P	Human genetics	1997	PMID: 9439663
https://www.pharmgkb.org/clinicalAnnotation/1447989706	-	-	-	-
https://www.pharmgkb.org/variant/PA166153649	-	-	-	-

Text-mined citations for rs1801266 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000110.4(DPYD):c.703C>T (p.Arg235Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801266 ...