rs55886062
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PP5_Strong
The NM_000110.4(DPYD):c.1679T>G(p.Ile560Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 0 hom. )
Consequence
DPYD
NM_000110.4 missense
NM_000110.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 8.76
Genes affected
DPYD (HGNC:3012): (dihydropyrimidine dehydrogenase) The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.832
PP5
?
Variant 1-97515787-A-C is Pathogenic according to our data. Variant chr1-97515787-A-C is described in ClinVar as [drug_response]. Clinvar id is 88975.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=5, Likely_pathogenic=2, drug_response=4}. Variant chr1-97515787-A-C is described in Lovd as [Pathogenic]. Variant chr1-97515787-A-C is described in Lovd as [Benign]. Variant chr1-97515787-A-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DPYD | NM_000110.4 | c.1679T>G | p.Ile560Ser | missense_variant | 13/23 | ENST00000370192.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DPYD | ENST00000370192.8 | c.1679T>G | p.Ile560Ser | missense_variant | 13/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000388 AC: 59AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000319 AC: 80AN: 250646Hom.: 0 AF XY: 0.000310 AC XY: 42AN XY: 135408
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ClinVar
Significance: drug response
Submissions summary: Pathogenic:10Other:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | DPYD: PS3:Very Strong, PM2 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| not provided, no classification provided | literature only | Diasio Lab, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2023 | Identified in the heterozygous state in patients with partial DPD deficiency, including patients who experienced 5-FU toxicity during cancer treatment (Collie-Duguid et al., 2000; Thomas et al., 2016); Published functional studies demonstrate that this variant reduces DPD enzyme activity (Offer et al., 2013); 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: 25381393, 23328581, 11895907, 19795123, 26603945, 10803677, 26265035, 32595208) - |
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 29, 2021 | Variant summary: DPYD c.1679T>G (p.Ile560Ser) results in a non-conservative amino acid change located in the dihydroorotate dehydrogenase domain (IPR005720) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 250646 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (0.00032 vs 0.0025), allowing no conclusion about variant significance. The variant, c.1679T>G (also described as DPYD*13), has been reported in the literature in a compound heterozygous individual affected with childhood onset Dihydropyrimidine Dehydrogenase Deficiency (van Kuilenburg 2002), and in other compound heterozygous individuals who had severe 5-fluorouracil toxicity following chemotherapy, but not other clinical symptoms or abnormalities were noted (Johnson_2002, Thomas_2015). In addition, the variant was also reported in several heterozygous individuals affected with 5-fluorouracil toxicity following chemotherapy (see e.g. Thomas_2015), and a meta-analysis found that the variant in heterozygosity was significantly associated with fluoropyrimidine-associated toxicity (adjusted relative risk (RR): 4.40, 95% CI: 2.08-9.30, p<0.0001), though the presence of this variant does not always resulted in toxicity (Meulendijks_2015). Experimental evidence evaluating an impact on protein function demonstrated that the variant resulted in a decreased enzyme activity, corresponding to about 75% reduction relative to the WT (Offer_2014), in addition, enzyme activity measured from patient derived peripheral blood mononuclear cells (PBMs) in a compound heterozygous patient was found almost undetectably low (van Kuilenburg 2002). Several Pharmacogenetics groups, including the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Dutch Pharmacogenetics Working Group (DPWG), and the Swiss Group of Pharmacogenomics and Personalised Therapy (SPT), released recent guidelines, considering this variant to be a 'non-functional' allele (with an activity score of 0), and strongly recommending DPYD genotyping for this and a few other variants, prior to the start of therapy with fluoropyrimidines, and a reduction of the initial dose in genotyped-positive patients in order to decrease the risk of fluoropyrimidine-induced toxicity (Caudle_2013, Amstutz_2018, Lunenburg_2020, Hamzic_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | 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 and 5-fluorouracil toxicity (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 11783493). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 88 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated dihydroorotate dehydrogenase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals and it is also a known risk for 5-fluorouracil toxicity (ClinVar, LOVD, PMIDs: 11895907, 11783493, 26603945). As DPYD variants that result in reduced enzyme function place individuals at risk of fluoropyrimidine toxicity, formal pharmocogenomic studies are recommended prior to treatment with fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies show up to a 75% reduction in activity relative to wild-type (PMID: 23328581, 29152729). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2016 | - - |
tegafur response - Toxicity Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | May 26, 2021 | 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. Drug-variant association: Toxicity |
fluorouracil response - Toxicity Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | May 24, 2021 | 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. Drug-variant association: Toxicity |
fluorouracil response - Other Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | May 24, 2021 | 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. Drug-variant association: Other |
capecitabine response - Toxicity Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | May 24, 2021 | 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. Drug-variant association: Toxicity |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at