GeneBe

rs55886062

Positions:

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

Scores

9
9
1

Clinical Significance

drug response reviewed by expert panel P:11O:5

Conservation

PhyloP100: 8.76
Variant links:
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: {Likely_pathogenic=3, not_provided=1, drug_response=4, Pathogenic=5}. 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 Protein UniProt
DPYDNM_000110.4 linkuse as main transcriptc.1679T>G p.Ile560Ser missense_variant 13/23 ENST00000370192.8 NP_000101.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DPYDENST00000370192.8 linkuse as main transcriptc.1679T>G p.Ile560Ser missense_variant 13/231 NM_000110.4 ENSP00000359211 P1Q12882-1

Frequencies

GnomAD3 genomes
AF:
0.000388
AC:
59
AN:
152012
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000658
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000706
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000319
AC:
80
AN:
250646
Hom.:
0
AF XY:
0.000310
AC XY:
42
AN XY:
135408
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.000654
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.000682
AC:
997
AN:
1460868
Hom.:
0
Cov.:
32
AF XY:
0.000632
AC XY:
459
AN XY:
726764
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.000853
Gnomad4 OTH exome
AF:
0.000663
GnomAD4 genome
AF:
0.000388
AC:
59
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000706
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000632
Hom.:
0
Bravo
AF:
0.000325
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000346
AC:
42
EpiCase
AF:
0.000655
EpiControl
AF:
0.000830

ClinVar

Significance: drug response
Submissions summary: Pathogenic:11Other:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:5Other:1
not provided, no classification providedliterature onlyDiasio Lab, Mayo Clinic-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2022DPYD: PS3:Very Strong, PM2 -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 07, 2024Identified in the heterozygous state in patients with partial DPD deficiency, including patients who experienced 5-FU toxicity during cancer treatment (PMID: 10803677, 26265035); Published functional studies demonstrate that this variant reduces DPD enzyme activity (PMID: 23328581); 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, 11895907, 19795123, 26603945, 37101114, 26265035, 32595208, 10803677, 23328581) -
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based 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 -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 29, 2021Variant 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 submitterclinical testingCounsylApr 28, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2024- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 27, 2022- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 05, 2024The c.1679T>G (p.I560S) alteration is located in exon 13 (coding exon 13) of the DPYD gene. This alteration results from a T to G substitution at nucleotide position 1679, causing the isoleucine (I) at amino acid position 560 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.031% (88/282028) total alleles studied. The highest observed frequency was 0.062% (80/128610) of European (non-Finnish) alleles. This alteration was detected in conjunction with another alteration in DPYD in multiple individuals with Dihydropyrimidine dehydrogenase deficiency (van Kuilenburg, 2000; Johnson, 2002; Thomas, 2016). This amino acid position is highly conserved in available vertebrate species. In an assay testing DPYD function, this variant showed a functionally abnormal result (Offer, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
tegafur response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMay 26, 2021PharmGKB 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 panelcurationPharmGKBMay 24, 2021PharmGKB 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 panelcurationPharmGKBMay 24, 2021PharmGKB 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 panelcurationPharmGKBMay 24, 2021PharmGKB 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
-0.024
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-5.1
D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.96
MVP
0.99
MPC
0.39
ClinPred
0.82
D
GERP RS
5.2
Varity_R
0.70
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs55886062; hg19: chr1-97981343; COSMIC: COSV104426937; API