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

gnomAD frequency: 0.00474  dbSNP: rs3918290

Total submissions: 24

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 Inc	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
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/.