VCV000635267.4 - ClinVar

NM_000110.4(DPYD):c.2983G>T (p.Val995Phe)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 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.2983G>T (p.Val995Phe)

Variation ID: 635267 Accession: VCV000635267.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97079071 (GRCh38) [ NCBI UCSC ] 1: 97544627 (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	Jul 1, 2019	Jan 6, 2024	Mar 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.2983G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000101.2:p.Val995Phe	missense
NC_000001.11:g.97079071C>A
NC_000001.10:g.97544627C>A
NG_008807.2:g.846989G>T
LRG_722:g.846989G>T

... more HGVS ... less HGVS

Protein change

V995F

Other names

Canonical SPDI

NC_000001.11:97079070:C: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) 0.00000

Links

Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000613417 dbSNP: rs1801268 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	414	548

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
fluorouracil response - Other	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV000786704.3
Dihydropyrimidine dehydrogenase deficiency	Likely pathogenic (1)	criteria provided, single submitter	Nov 21, 2023	RCV003479218.1

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 (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: SCV000925526.2 First in ClinVar: Jul 01, 2019 Last updated: Dec 12, 2021	Publications: PubMed (2) PubMed: 10071185‚ 24648345 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153651 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1447989723 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)
Likely pathogenic (Nov 21, 2023)	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: SCV004223006.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 24648345‚ 9686374 Comment: Variant summary: DPYD c.2983G>T (p.Val995Phe) results in a non-conservative amino acid change located in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (IPR017896) of the encoded protein … (more) Variant summary: DPYD c.2983G>T (p.Val995Phe) results in a non-conservative amino acid change located in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.2983G>T has been reported in the literature in the homozygous state in an individual affected with Dihydropyrimidine Dehydrogenase Deficiency (Vreken_1998). At least two publications report experimental evidence evaluating an impact on protein function and found that the variant results in <12.5% enzymatic activity compared to the WT protein (e.g. Vreken_1998, Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24648345, 9686374). Based on the evidence outlined above, the variant was classified as likely pathogenic. (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:

Variant summary: DPYD c.2983G>T (p.Val995Phe) results in a non-conservative amino acid change located in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.2983G>T has been reported in the literature in the homozygous state in an individual affected with Dihydropyrimidine Dehydrogenase Deficiency (Vreken_1998). At least two publications report experimental evidence evaluating an impact on protein function and found that the variant results in <12.5% enzymatic activity compared to the WT protein (e.g. Vreken_1998, Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24648345, 9686374). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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
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
https://www.pharmgkb.org/clinicalAnnotation/1447989723	-	-	-	-
https://www.pharmgkb.org/variant/PA166153651	-	-	-	-

Text-mined citations for rs1801268 ...

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.2983G>T (p.Val995Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801268 ...