Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000393255 | SCV000795560 | uncertain significance | Dihydropyrimidine dehydrogenase deficiency | 2017-11-09 | criteria provided, single submitter | clinical testing | |
| Centogene AG - |
RCV000393255 | SCV001424404 | pathogenic | Dihydropyrimidine dehydrogenase deficiency | criteria provided, single submitter | clinical testing | ||
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000393255 | SCV001623227 | pathogenic | Dihydropyrimidine dehydrogenase deficiency | 2024-09-27 | criteria provided, single submitter | clinical testing | Variant summary: DPYD c.1475C>T (p.Ser492Leu) results in a non-conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) 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 4.4e-05 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.1475C>T has been reported in the literature in homozygous individuals affected with Dihydropyrimidine Dehydrogenase Deficiency (e.g. Van Kuilenburg_2002, Cheema_2020). The variant has also been reported as heterozygous in at least one individual who exhibited signs of toxicity upon treatment with capecitabine (e.g. Milano_2016, Etienee-Grimaldi_2017). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant resulted in nearly absent enzyme activity in homozygous patient cells and substantially reduced activity (~18% of wild type) when expressed in an isogenic cell line (e.g. Van Kuilenburg_2002, Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24648345, 11988088, 24590654, 31745289, 32707991, 32899374, 28481884, 12912951, 27454530, 17046731, 33083013). ClinVar contains an entry for this variant (Variation ID: 298293). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000393255 | SCV004194073 | likely pathogenic | Dihydropyrimidine dehydrogenase deficiency | 2024-03-09 | criteria provided, single submitter | clinical testing | |
| Pittsburgh Clinical Genomics Laboratory, |
RCV000393255 | SCV005397299 | likely pathogenic | Dihydropyrimidine dehydrogenase deficiency | 2022-02-08 | criteria provided, single submitter | clinical testing | This sequence variant is a single nucleotide substitution (C>T) which results in a serine to leucine amino acid change at residue 492 of the DPYD protein. This is a previously reported variant (ClinVar) which has been reported in homozygous state in an individual with complete dihydropyrimidine dehydrogese deficiency (PMID: 11988088) and in heterozygous state in an individual with grade 4 toxicity to capecitabine (PMID: 28481884). This variant is rare in the gnomAD control population dataset (13/282442 alleles or 0.005%). Multiple bioinformatic tools predict that this serine to leucine amino acid change will be damaging, and serine is highly conserved at this protein position in vertebrates. Functiol studies suggest that the variant protein has significantly decreased dihydropyrimidine dehydrogese activity decreased compared to wild-type protein (PMID: 11988088, 24648345). Ser492 is in the FAD cofactor binding site, and protein crystal structure alysis suggests that substituting leucine at this position inhibits FAD interaction (PMID: 11988088). Given the available evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP3, PS3 |