ClinVar Miner

Submissions for variant NM_000110.3(DPYD):c.1905+1G>A (rs3918290)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735355 SCV000854509 pathogenic Autistic disorder of childhood onset; Macroglossia; Global developmental delay; Seizures; Hallux valgus; Cognitive impairment; Aggressive behavior; Coarse facial features; Mandibular prognathia; 2-3 toe syndactyly; Bulbous nose; Frontal bossing; Thick lower lip vermilion; Widely spaced teeth; Intellectual disability; Short toe; Clinodactyly of the 5th toe; Intellectual disability, profound; Abnormal aggressive, impulsive or violent behavior; Slit-like opening of the exterior auditory meatus; Shortening of all phalanges of fingers; Profound global developmental delay criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000086468 SCV000610939 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing
Counsyl RCV000000460 SCV000486085 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-03-24 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000000460 SCV000744672 uncertain significance Dihydropyrimidine dehydrogenase deficiency 2017-04-19 criteria provided, single submitter clinical testing
Department of Genetics, Reproduction and Fetal Medicine.,Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville. RCV000201291 SCV000222717 uncertain significance Hirschsprung disease 1 2015-04-01 no assertion criteria provided research
Diasio Lab, Mayo Clinic RCV000086468 SCV000118634 not provided not provided no assertion provided not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000086468 SCV000225998 pathogenic not provided 2015-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000086468 SCV000329338 pathogenic not provided 2017-07-24 criteria provided, single submitter clinical testing The c.1905+1G>A pathogenic variant in the DPYD gene has been reported previously in the homozygous state in individuals with variable features of dihydropyrimidine dehydrogenase deficiency, but has also been reported homozygous in asymptomatic individuals (Vreken et al., 1996; Au et al., 2003; Zhu et al., 2015). The c.1905+1G>A variant (also referred to as DPYD*2A) is also one of the most common DPYD variants reported in association with toxicity to 5-fluorouracil, both in the heterozygous and biallelic state (Kleibl et al., 2009; Johnson et al., 2002; Falvella et al., 2015). The c.1905+1G>A splice site variant destroys the canonical splice donor site in intron 14. Functional studies demonstrate that this variant leads to a 165-bp deletion (corresponding to exon 14) of the DPYD mRNA, which is translated into a nonfunctional DPYD protein (Vreken et al., 1996; Johnson et al., 2002; Offer et al., 2013). The c.1905+1G>A variant is observed in 144/6,608 (2.21%) alleles from individuals of European (Finnish) background including multiple unrelated homozygous individuals in the ExAC dataset, which is greater than expected for this disorder (Lek et al., 2016). We interpret c.1905+1G>A as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000030868 SCV000594401 pathogenic Fluorouracil response 2016-05-04 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000000460 SCV000743426 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-12-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000460 SCV000359589 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-06-14 criteria provided, single submitter clinical testing Across a selection of available literature, the c.1905+1G>A variant has been reported in at least 30 patients with dihydropyrimidine dehydrogenase deficiency, including in at least four patients in a homozygous state and in 26 patients in a heterozygous state, all of whom had 5-fluorouracil (5-FU) toxicity (Vreken et al. 1996; Van Kuilenburg et al. 1999; Van Kuilenburg et al. 2002; Morel et al. 2006; Magne et al. 2007). The c.1905+1G>A variant was found in one of 74 controls and is reported at a frequency of 0.02209 in the European (Finnish) population of the Exome Aggregation Consortium. The DPYD c.1905+1G>A variant occurs in a canonical splice site (donor) and results in skipping of exon 14 leading to an inactive DPYD allele (Wei et al. 1996). In patients with the c.1905+1G>A variant in a heterozygous state, conversion of 5-FU was shown to be 40% lower compared to controls (Van Kuilenburg et al. 2012). Based on the collective evidence, the c.1905+1G>A variant is classified as pathogenic for dihydropyrimidine dehydrogenase deficiency.
Integrated Genetics/Laboratory Corporation of America RCV000000460 SCV000695411 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-01-18 criteria provided, single submitter clinical testing
OMIM RCV000000460 SCV000020609 pathogenic Dihydropyrimidine dehydrogenase deficiency 1999-01-01 no assertion criteria provided literature only
OMIM RCV000030868 SCV000020610 pathogenic Fluorouracil response 1999-01-01 no assertion criteria provided literature only
PharmGKB RCV000660822 SCV000783061 drug response capecitabine response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000660823 SCV000783062 drug response fluorouracil response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000660824 SCV000783063 drug response Pyrimidine analogues response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000660825 SCV000783064 drug response tegafur response - Toxicity/ADR, Metabolism/PK 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.

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