NM_000110.3(DPYD):c.1905+1G>A AND Dihydropyrimidine dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Jun 1, 2015)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000000460.2

Allele description [Variation Report for NM_000110.3(DPYD):c.1905+1G>A]

NM_000110.3(DPYD):c.1905+1G>A

Gene:
DPYD:dihydropyrimidine dehydrogenase [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
1p21.3
Genomic location:
Preferred name:
NM_000110.3(DPYD):c.1905+1G>A
HGVS:
  • NC_000001.11:g.97450058C>T
  • NG_008807.2:g.476002G>A
  • NM_000110.3:c.1905+1G>A
  • NC_000001.10:g.97915614C>T
  • NC_000001.9:g.97688202C>T
Note:
NCBI staff reviewed the sequence information reported in PubMed 8892022 Fig. 3 to determine the location of this allele on the current reference sequence.
Nucleotide change:
IVS14, G-A, +1
Links:
OMIM: 612779.0001; dbSNP: 3918290
GMAF:
0.0030(T), 3918290
NCBI 1000 Genomes Browser:
rs3918290
Allele Frequency:
0.0042, GO-ESP
Molecular consequence:
  • NM_000110.3:c.1905+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
2

Condition(s)

Name:
Dihydropyrimidine dehydrogenase deficiency
Synonyms:
DPYD DEFICIENCY; DPD deficiency; Thymine Uraciluria hereditary; See all synonyms [MedGen]
Identifiers:
MedGen: C2720286; OMIM: 274270

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000020609OMIMno assertion criteria providedPathogenic
(Mar 12, 2013)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

SCV000225998Emory Genetics Laboratorycriteria provided, single submitter
(EGL Classification Definitions)
Pathogenic
(Jun 1, 2015)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea.

Meinsma R, Fernandez-Salguero P, Van Kuilenburg AB, Van Gennip AH, Gonzalez FJ.

DNA Cell Biol. 1995 Jan;14(1):1-6.

PubMed [citation]
PMID:
7832988

Clinical and biochemical findings in six patients with pyrimidine degradation defects.

van Gennip AH, Abeling NG, Stroomer AE, van Lenthe H, Bakker HD.

J Inherit Metab Dis. 1994;17(1):130-2. No abstract available.

PubMed [citation]
PMID:
8051923
See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000020609.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Emory Genetics Laboratory, SCV000225998.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

Last Updated: Jun 27, 2015