ClinVar Miner

Submissions for variant UGT1A1*28

dbSNP: rs3064744
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000249621 SCV000304404 benign not specified criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001093257 SCV000597831 other not provided 2021-02-10 criteria provided, single submitter clinical testing
Medical Genetics Summaries RCV000664404 SCV000788336 drug response Irinotecan response 2018-04-04 criteria provided, single submitter curation The risk of irinotecan toxicity increases with genetic variants associated with reduced UGT enzyme activity, such as UGT1A1*28. The presence of this variant results in reduced excretion of irinotecan metabolites, which leads to increased active irinotecan metabolites in the blood. Homozygous individuals (UGT1A1 *28/*28) are more likely to develop neutropenia following irinotecan therapy
Mendelics RCV000013065 SCV001136248 likely pathogenic Crigler-Najjar syndrome, type II 2023-06-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001093257 SCV001250152 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing UGT1A1: PS3, PS4, PP4:Moderate
Centogene AG - the Rare Disease Company RCV000013064 SCV001426572 pathogenic Gilbert syndrome criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001093257 SCV001714671 pathogenic not provided 2021-03-25 criteria provided, single submitter clinical testing
Invitae RCV001093257 SCV001723216 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This variant is located in the TATA box of the UGT1A1 promoter region. Variants altering TATA repeat length from its usual length of 6 TA repeats (aka (TA)6 or UGT1A1*1) are associated with Gilbert syndrome, a mild and often asymptomatic hyperbilirubinemia. This variant is present in population databases (rs34983651, gnomAD 40%), and has an allele count higher than expected for a pathogenic variant. This variant is known to be associated with Gilbert syndrome. Individuals who are heterozygous for this variant maintain approximately 70% of the residual enzyme activity (PMID: 7565971, 9435989, 16610035, 28520360). Individuals who are homozygous for this variant maintain approximately 30% residual enzyme activity and have elevated total bilirubin levels consistent with Gilbert syndrome (PMID: 7565971, 9435989, 11003624, 26467199). Compound heterozygosity for this variant and a pathogenic UGT1A1 coding variant may result in a more pronounced enzyme deficiency, higher total serum bilirubin levels, and a clinical presentation similar to Crigler-Najjar syndrome (PMID: 9639672, 11370628). This variant is also known as (TA)7 or UGT1A1*28. ClinVar contains an entry for this variant (Variation ID: 12275). Studies have shown that this variant alters UGT1A1 gene expression (PMID: 9639672). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001093257 SCV001915735 benign not provided 2019-10-02 criteria provided, single submitter clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000013064 SCV002505857 uncertain significance Gilbert syndrome 2021-08-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001093257 SCV002506315 pathogenic not provided 2022-11-29 criteria provided, single submitter clinical testing The UGT1A1 TATA box commonly has 6 TA repeats; however, there can be 5 TA repeats, 7 TA repeats, or less commonly, 8 and 9 TA repeats (Barbarino 2014). In vitro studies have shown that UGT1A1 promoter expression decreases as the number of TA repeats increases (Beutler 1998). Genotypes that are homozygous for (TA)7, homozygous for (TA)8, or compound heterozygotes for (TA)7, (TA)8, or (TA)9 cause reduced expression of UGT1A1 and are associated with Gilbert syndrome, which is characterized by increased bilirubin levels, and may have a neonatal appearance of hereditary spherocytosis (Bosma 1995, Iolascon 1998, Nikolac 2008, Ostanek 2007). Individuals who are heterozygous for the (TA)7 *28 promoter variant may have an increased risk for drug toxicity when treated with irinotecan (Marcuello 2004, Riera 2018). Individuals who are homozygous for (TA)7 or compound heterozygous for more than 6 TA repeats may experience an increased incidence of atazanavir-associated hyperbilirubinemia (Gammal 2016). References Barbarino JM et al. PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genomics. 2014 24:177-183. PMID: 24492252 Beutler E et al. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998 95:8170-8174. PMID: 9653159 Bosma PJ et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995 333:1171-1175. PMID: 7565971 Gammal RS et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 99:363-369. PMID: 26417955 Iolascon A et al. UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis. Blood. 1998 91:1093. PMID: 9446675 Marcuello E et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004 91:678-682. PMID: 15280927 Nikolac N et al. Rare TA repeats in promoter TATA box of the UDP glucuronosyltranferase (UGT1A1) gene in Croatian subjects. Clin Chem Lab Med. 2008 46:174-178. PMID: 18324905 Ostanek B et al. UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. Blood Cells Mol Dis. 2007 38:78-82. PMID: 17196409 Riera P et al. Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity. Br J Clin Pharmacol. 2018 84:1389-1392. PMID: 29504153
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000249621 SCV002761120 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV001093257 SCV002818175 pathogenic not provided 2022-12-17 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000013064 SCV004100783 pathogenic Gilbert syndrome 2023-09-19 criteria provided, single submitter clinical testing Criteria applied: PM3_VSTR,PS3
OMIM RCV000013064 SCV000033310 affects Gilbert syndrome 2009-04-01 no assertion criteria provided literature only
OMIM RCV000013065 SCV000033311 pathogenic Crigler-Najjar syndrome, type II 2009-04-01 no assertion criteria provided literature only
OMIM RCV000022808 SCV000044097 pathogenic Lucey-Driscoll syndrome 2009-04-01 no assertion criteria provided literature only
OMIM RCV000022809 SCV000044098 association Bilirubin, serum level of, quantitative trait locus 1 2009-04-01 no assertion criteria provided literature only
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV001269334 SCV001448279 pathogenic Bilirubin, serum level of, quantitative trait locus 1; Crigler-Najjar syndrome type 1; Lucey-Driscoll syndrome; Crigler-Najjar syndrome, type II; Gilbert syndrome 2020-10-04 flagged submission clinical testing

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