Submissions for variant NM_000110.4(DPYD):c.257C>T (p.Pro86Leu)

gnomAD frequency: 0.00004  dbSNP: rs568132506

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001329029	SCV001520321	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2024-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001551714	SCV001772281	likely pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in individuals who developed partial DPD deficiency and toxicity when exposed to fluorouracil, a chemotherapy drug (Del Re et al., 2016; Thomas et al., 2016); Published functional studies demonstrate a damaging effect with a significant reduction in enzyme activity compared with wild type (Elraiyah et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27727460, 15591715, 17046731, 15450176, 28128059, 11988088, 12851836, 30349988, 11783493, 26265035, 15377401, 26651493, 32529295, 34449540, 34426522, 35089958)
Revvity Omics, Revvity	RCV001329029	SCV002017326	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2021-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001329029	SCV002500413	pathogenic	Dihydropyrimidine dehydrogenase deficiency	2022-03-16	criteria provided, single submitter	clinical testing	Variant summary: DPYD c.257C>T (p.Pro86Leu) results in a non-conservative amino acid change located in the Domain I (Elraiyah_2017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251076 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (5.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.257C>T has been reported in the literature as a homozygous, compound heterozygous and apparently homozygous (UPD chromosome 1) genotype in at-least three individuals affected with Dihydropyrimidine dehydrogenase deficiency (example, Van Kuilenberg_2000, 2002, 2019), Del Re_2016) and has been subsequently cited by others (example, Elraiyah_2017). These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Van Kuilenberg_2002, Elraiyah_2017, Van Kuilenberg_2019). The most pronounced variant effect results in complete absence (1%) of normal Dihydropyrimidine dehydrogenase (DPD) enzyme activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001329029	SCV002549821	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2022-06-10	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4_MOD, PP3
Fulgent Genetics, Fulgent Genetics	RCV001329029	SCV002814283	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2022-03-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001551714	SCV004042438	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	DPYD: PS3:Very Strong, PS4:Moderate, PP3
Genome-Nilou Lab	RCV001329029	SCV004049897	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001329029	SCV004806324	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2024-03-25	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001329029	SCV005045131	likely pathogenic	Dihydropyrimidine dehydrogenase deficiency	2024-03-22	criteria provided, single submitter	clinical testing	The DPYD c.257C>T (p.Pro86Leu) variant has been observed in at least four individuals affected with dihydropyrimidine dehydrogenase deficiency in the homozygous and compound heterozygous states (Elraiyah Y et al., PMID: 27727460; Del Re M et al., PMID: 26651493; van Kuilenburg ABP et al., PMID: 30349988; van Kuilenburg AB et al., 11783493; van Kuilenburg AB et al., PMID: 11988088). This variant is only observed on 15/282,466 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies show reduced or abolished enzyme activity, indicating that this variant impacts protein function (Elraiyah T et al., PMID: 27727460; van Kuilenburg ABP et al., PMID: 30349988). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to DPYD function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.