ClinVar Miner

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

gnomAD frequency: 0.00474  dbSNP: rs3918290
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787337 SCV000783062 drug response fluorouracil response - Toxicity 2021-05-24 reviewed by expert panel curation 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.
PharmGKB RCV001787360 SCV002031279 drug response capecitabine response - Toxicity 2021-05-24 reviewed by expert panel curation 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.
PharmGKB RCV001787359 SCV002031280 drug response fluorouracil response - Other 2021-05-24 reviewed by expert panel curation 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.
PharmGKB RCV001787361 SCV002031281 drug response tegafur response - Toxicity 2021-05-24 reviewed by expert panel curation 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.
Eurofins Ntd Llc (ga) RCV000086468 SCV000225998 pathogenic not provided 2015-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000086468 SCV000329338 pathogenic not provided 2022-07-31 criteria provided, single submitter clinical testing Individuals who carry at least one DPYD c.1905+1G>A allele are at risk to experience drug toxicity when treated with fluoropyrimidine drugs. Dosing guidelines based on DPYD genotype are available (Amstutz et al., 2018); Published functional studies demonstrate variant results in a nonfunctional DPYD protein (Offer et al., 2013); This variant is associated with the following publications: (PMID: 24700034, 19178088, 25525159, 11895907, 8892022, 12668826, 22975760, 25906475, 25087612, 22339448, 21114665, 15093568, 19473056, 26804652, 25590979, 26559152, 26603945, 30609409, 31124962, 30775324, 31980526, 33326653, 30755392, 32595208, 33877893, 23328581, 34426522, 34026625, 29152729, 34697415)
Illumina Laboratory Services, 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.
Counsyl RCV000000460 SCV000486085 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-03-24 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000030868 SCV000594401 pathogenic Fluorouracil response 2016-05-04 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000460 SCV000695411 pathogenic Dihydropyrimidine dehydrogenase deficiency 2016-01-18 criteria provided, single submitter clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles RCV000735355 SCV000854509 pathogenic Autism; Macroglossia; Global developmental delay; Seizure; 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
Athena Diagnostics RCV000086468 SCV001143792 pathogenic not provided 2019-07-09 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is more than 10 times the disease allele frequency. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families
Baylor Genetics RCV000000460 SCV001162929 pathogenic Dihydropyrimidine dehydrogenase deficiency criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000086468 SCV001247769 pathogenic not provided 2024-01-01 criteria provided, single submitter clinical testing DPYD: PP1:Strong, PM3, PS3:Moderate, PVS1:Moderate, PM2:Supporting, PP4
Centogene AG - the Rare Disease Company RCV000000460 SCV002028339 pathogenic Dihydropyrimidine dehydrogenase deficiency 2021-11-01 criteria provided, single submitter clinical testing
3billion RCV000000460 SCV002058930 pathogenic Dihydropyrimidine dehydrogenase deficiency 2022-01-03 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000432, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000000460 SCV002767928 pathogenic Dihydropyrimidine dehydrogenase deficiency 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with biallelic variants are well reported (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient cell-derived RNA demonstrates that this variant results in exon 14 skipping. This results in an inframe deletion, and the protein product p.(Asp581_Asn635del) (PMID: 8892022). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1590 heterozygotes, 9 homozygotes). (I) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in homozygous and compound heterozygous patients with dihydropyrimidine dehydrogenase deficiency (ClinVar, PMID: 8892022, PMID: 28929491). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient fibroblasts homozygous for this variant have been shown with no detectable enzyme activity (PMID: 8892022). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000000460 SCV004804714 likely pathogenic Dihydropyrimidine dehydrogenase deficiency 2024-03-17 criteria provided, single submitter research
Ambry Genetics RCV004018525 SCV004859742 pathogenic Inborn genetic diseases 2021-03-09 criteria provided, single submitter clinical testing 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.
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
Diasio Lab, Mayo Clinic RCV000086468 SCV000118634 not provided not provided no assertion provided not provided
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, susceptibility to, 1 2015-04-01 no assertion criteria provided research
GenomeConnect - Brain Gene Registry RCV000000460 SCV004012817 not provided Dihydropyrimidine dehydrogenase deficiency no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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