Submissions for variant UGT1A1*28

dbSNP: rs3064744

Total submissions: 21

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	2024-06-01	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	2023-06-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-07-31	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	2022-08-12	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM3
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000013064	SCV005187248	pathogenic	Gilbert syndrome		criteria provided, single submitter	clinical testing	This variant in the promoter region of UGT1A1 is associated with reduced transcription of UGT1A1 (Hsieh TY et al 2007).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001269334	SCV005417937	uncertain significance	Bilirubin, serum level of, quantitative trait locus 1; Crigler-Najjar syndrome type 1; Lucey-Driscoll syndrome; Crigler-Najjar syndrome, type II; Gilbert syndrome		criteria provided, single submitter	clinical testing	BS1+PS3_Supporting+PM3+PP4
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