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NM_000110.4(DPYD):c.1905+1G>A AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 9, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004018525.1

Allele description [Variation Report for NM_000110.4(DPYD):c.1905+1G>A]

NM_000110.4(DPYD):c.1905+1G>A

Gene:
DPYD:dihydropyrimidine dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p21.3
Genomic location:
Preferred name:
NM_000110.4(DPYD):c.1905+1G>A
Other names:
DPYD*2A
HGVS:
  • NC_000001.11:g.97450058C>T
  • NG_008807.2:g.476002G>A
  • NM_000110.3(DPYD):c.1905+1G>A
  • NM_000110.4:c.1905+1G>AMANE SELECT
  • LRG_722t1:c.1905+1G>A
  • LRG_722:g.476002G>A
  • NC_000001.10:g.97915614C>T
  • NC_000001.9:g.97688202C>T
  • NM_000110.3(DPYD):c.1905+1G>A
  • NM_000110.3:c.1905+1G>A
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:
Genetic Testing Registry (GTR): GTR000613302; PharmGKB: 827843617PA128406956; PharmGKB: 827843617PA164713220; PharmGKB: 827843617PA448771; PharmGKB: 827843617PA452620; PharmGKB Clinical Annotation: 827843617; OMIM: 612779.0001; dbSNP: rs3918290
NCBI 1000 Genomes Browser:
rs3918290
Molecular consequence:
  • NM_000110.4:c.1905+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Functional consequence:
exon loss [PubMedVariation Ontology: 0381]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004859742Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Mar 9, 2021) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Nothing to display

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV004859742.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The c.1905+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the DPYD gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DPYD c.1905+1G>A alteration was observed in 0.57% (1608/282660) of total alleles studied including 9 homozygotes, with a frequency of 2.38% (599/25120) in the European (Finnish) subpopulation. This alteration (also referred to as DYPD*2A) has been reported in the homozygous and compound heterozygous states in patients with DPD deficiency and variable phenotypes including neurological disorders and 5-fluorouracil toxicity (Vreken, 1996; Johnson, 2002; Zhu, 2015). This nucleotide position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in exon 14 skipping, undetectable enzyme activity and inability to convert 5-FU to DHFU leading to 5-florouracil toxicity (Vreken, 1996; Johnson, 2002; Offer, 2013). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Nov 18, 2024