ClinVar Genomic variation as it relates to human health

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 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 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 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.

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.

Identified 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)

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

The 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.

DPYD: PS3:Very Strong, PM2