Submissions for variant UGT1A1*37

dbSNP: rs3064744

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics Summaries	RCV000664405	SCV000788337	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*37.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508486	SCV001714672	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001508486	SCV001884561	benign	not provided	2020-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001508486	SCV002161949	pathogenic	not provided	2024-01-26	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 (no rsID available, gnomAD 5%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in trans with the c.-41_-40dup (also known as (TA)7 or UGT1A1*28) variant in individual(s) with Gilbert syndrome (PMID: 10091406, 15205079). It has also been observed to segregate with disease in related individuals. 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. This variant is also known as (TA)8, UGT1A1*37. ClinVar contains an entry for this variant (Variation ID: 549829). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant decreases UGT1A1 promoter activity (PMID: 9653159). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001508486	SCV003799419	pathogenic	not provided	2023-10-20	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	RCV004596322	SCV005089791	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892146	SCV004117773	uncertain significance	UGT1A9-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The UGT1A9 c.856-6789_856-6786dupTATA variant is predicted to result in an intronic duplication. The common allele in the general population is A(TA)6TAA; therefore, this individual has two additional TA repeats in this region. The c.-43_-40dup variant found in this patient is equivalent to the A(TA)8TAA allele in the literature. One TA repeat in this region (also referred to as c.-41_-40dup or A(TA)7TAA allele) resulted in reduced expression of bilirubin UDP-glucuronosyltransferase 1 and subsequently increased serum bilirubin levels, and is considered an established risk factor for hyperbilirubinemia and Gilbert syndrome. The activity of the UGT1A1 promoter was shown to decrease with a progressively increasing number of TA repeat in one in vitro study (Beutler et al. 1998. PubMed ID: 9653159), although repeat variants other than the A(TA)7TAA allele have not been well-characterized to date. The allele frequency of the c.-43_-40dup (i.e. the A(TA)8TAA allele) was also reported at nearly 7% in the same study (Beutler et al. 1998. PubMed ID: 9653159). In the gnomAD database, the c.-43_-40dup variant was listed at a minor allele frequency of up to ~5.3% in the African population, including 12 homozygotes. In summary, although we suspect that this variant is benign in the context of severe Mendelian disease, we cannot rule out the possibility that this variant may act as a contributing risk factor for a more mild clinical presentation similar to the c.-41_-40dup risk variant. Therefore, we classify c.-43_-40dupTATA as a variant of uncertain significance in the absence of conclusive genetic and functional evidence.