VCV000287480.15 - ClinVar

NM_000110.4(DPYD):c.2303C>A (p.Thr768Lys)

Germline

Top reviewed classifications are shown here.

Submission summary:

8 submissions

8 submitters

5 conditions

Reviewed by expert panel

Drug response

May 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.2303C>A (p.Thr768Lys)

Variation ID: 287480 Accession: VCV000287480.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97234991 (GRCh38) [ NCBI UCSC ] 1: 97700547 (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	Oct 8, 2024	May 25, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.2303C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000101.2:p.Thr768Lys	missense
NC_000001.11:g.97234991G>T
NC_000001.10:g.97700547G>T
NG_008807.2:g.691069C>A
LRG_722:g.691069C>A
LRG_722t1:c.2303C>A	LRG_722p1:p.Thr768Lys

... more HGVS ... less HGVS

Protein change

T768K

Other names

Canonical SPDI

NC_000001.11:97234990:G:T

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.

0.00020 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00014

1000 Genomes Project 30x 0.00016

Exome Aggregation Consortium (ExAC) 0.00019

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00021

Links

ClinGen: CA963062 dbSNP: rs56005131 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
DPYD-AS1	-	-	-	GRCh38	-	111

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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 2, 2020	RCV000281091.6
Dihydropyrimidine dehydrogenase deficiency	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 15, 2017	RCV000671369.8
fluorouracil response - Other	drug response (1)	reviewed by expert panel	May 25, 2021	RCV001788190.1
DPYD-related disorder	Likely benign (1)	no assertion criteria provided	Apr 13, 2020	RCV003920127.2
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Mar 2, 2021	RCV002518984.2

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 (May 25, 2021)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Other Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031285.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Publications: PubMed (1) PubMed: 29769267 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166179517 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1449575645 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 (Mar 02, 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: SCV003684850.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution … (more) The c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution at nucleotide position 2303, causing the threonine (T) at amino acid position 768 to be replaced by a lysine (K). The in silico prediction for the p.T768K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely benign (Dec 15, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000796338.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (5) PubMed: 23596069‚ 17876700‚ 17828463‚ 16033824‚ 24648345
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001253063.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 17828463‚ 16033824 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 14, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000341264.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	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: 1 Sex: mixed
Uncertain significance (Sep 02, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001778862.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura … (more) Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura et al., 2005); Functional studies are discordant in their conclusions regarding enzyme activity (Offer et al., 2014; Ogura et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in 3-6% of Japanese individuals (Maekawa et al., 2007; Okamoto et al., 2007); This variant is associated with the following publications: (PMID: 29769267, 20920994, 17876700, 19287123, 17828463, 24163242, 21498394, 16033824, 24648345, 32619063, 32707991) (less)
Likely benign (Apr 13, 2020)	no assertion criteria provided Method: clinical testing	DPYD-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004731310.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (-)	no classification provided Method: phenotyping only	Dihydropyrimidine dehydrogenase deficiency Affected status: unknown Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV000840326.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Overgrowth (present) , Abnormality of the skull (present) , Abnormality of … (more) Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Overgrowth (present) , Abnormality of the skull (present) , Abnormality of the oral cavity (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Cognitive impairment (present) , Morphological abnormality of the central nervous system (present) , Autistic behavior (present) , Short attention span (present) , Obsessive-compulsive behavior (present) , Generalized abnormality of skin (present) , Joint hypermobility (present) , Abnormality of muscle physiology (present) , EMG abnormality (present) , Syncope (present) , Abnormal EKG (present) , Arrhythmia (present) , Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Abnormal inflammatory response (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Abnormality of thrombocytes (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: Courtagen Diagnostics Laboratory,Courtagen Life Sciences Date variant was reported to submitter: 2017-01-26 Testing laboratory interpretation: Uncertain significance

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 c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution at nucleotide position 2303, causing the threonine (T) at amino acid position 768 to be replaced by a lysine (K). The in silico prediction for the p.T768K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura et al., 2005); Functional studies are discordant in their conclusions regarding enzyme activity (Offer et al., 2014; Ogura et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in 3-6% of Japanese individuals (Maekawa et al., 2007; Okamoto et al., 2007); This variant is associated with the following publications: (PMID: 29769267, 20920994, 17876700, 19287123, 17828463, 24163242, 21498394, 16033824, 24648345, 32619063, 32707991)

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
Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals.	Hishinuma E	Drug metabolism and disposition: the biological fate of chemicals	2018	PMID: 29769267
Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity.	Offer SM	Cancer research	2014	PMID: 24648345
Targeted exome sequencing of suspected mitochondrial disorders.	Lieber DS	Neurology	2013	PMID: 23596069
SSCP screening of the dihydropyrimidine dehydrogenase gene polymorphisms of the Japanese population using a semi-automated electrophoresis unit.	Okamoto Y	Biochemical genetics	2007	PMID: 17876700
Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences.	Maekawa K	Journal of human genetics	2007	PMID: 17828463
Dihydropyrimidine dehydrogenase activity in 150 healthy Japanese volunteers and identification of novel mutations.	Ogura K	Clinical cancer research : an official journal of the American Association for Cancer Research	2005	PMID: 16033824
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DPYD	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1449575645	-	-	-	-
https://www.pharmgkb.org/variant/PA166179517	-	-	-	-

Text-mined citations for rs56005131 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000110.4(DPYD):c.2303C>A (p.Thr768Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56005131 ...