UGT1A1*28 AND not provided

Germline classification:: Conflicting interpretations of pathogenicity; other (6 submissions)
Last evaluated:: Sep 12, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001093257.48

Allele description [Variation Report for UGT1A1*28]

UGT1A1*28

Genes:

UGT1A1:UDP glucuronosyltransferase family 1 member A1 [Gene - OMIM - HGNC]
UGT1A:UDP glucuronosyltransferase family 1 member A complex locus [Gene - HGNC]
UGT1A10:UDP glucuronosyltransferase family 1 member A10 [Gene - OMIM - HGNC]
UGT1A3:UDP glucuronosyltransferase family 1 member A3 [Gene - OMIM - HGNC]
UGT1A4:UDP glucuronosyltransferase family 1 member A4 [Gene - OMIM - HGNC]
UGT1A5:UDP glucuronosyltransferase family 1 member A5 [Gene - OMIM - HGNC]
UGT1A6:UDP glucuronosyltransferase family 1 member A6 [Gene - OMIM - HGNC]
UGT1A7:UDP glucuronosyltransferase family 1 member A7 [Gene - OMIM - HGNC]
UGT1A8:UDP glucuronosyltransferase family 1 member A8 [Gene - OMIM - HGNC]
UGT1A9:UDP glucuronosyltransferase family 1 member A9 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

2q37.1

Genomic location:

Preferred name:

UGT1A1*28

Other names:

A(TA)7TAA; (TA)7TAA; c.-53_-52insTA,A(TA)7TAA,UGT1A1*28; TA7; *28

HGVS:

NC_000002.12:g.233760235TA[8]
NG_002601.2:g.175492TA[8]
NG_033238.1:g.4963TA[8]
NM_001072.4:c.862-6800AT[8]MANE SELECT
NM_007120.3:c.868-6800AT[8]MANE SELECT
NM_019075.4:c.856-6800AT[8]MANE SELECT
NM_019076.5:c.856-6800AT[8]MANE SELECT
NM_019077.3:c.856-6800AT[8]MANE SELECT
NM_019078.2:c.868-6800AT[8]MANE SELECT
NM_019093.4:c.868-6800AT[8]MANE SELECT
NM_021027.3:c.856-6800AT[8]MANE SELECT
NM_205862.3:c.61-6800AT[8]
LRG_733t1:c.-41_-40dup
LRG_733:g.4963TA[8]
NC_000002.11:g.234668879_234668880insAT
NC_000002.11:g.234668881TA[8]
NC_000002.11:g.234668893_234668894dup
NC_000002.11:g.234668893_234668894dupTA
NM_000463.2:c.-41_-40dupTA
NM_000463.3:c.-40_-39insTAMANE SELECT
NM_000463.3:c.-41_-40dupMANE SELECT
NM_000463.3:c.-41_-40dupTAMANE SELECT
NM_000463.3:c.-55_-54insATMANE SELECT
NM_019093.4:c.868-6787_868-6786dupTAMANE SELECT

Note:

Until October 16, 2017, this allele had conflicting molecular definitions. UGT1A1*28 is the allele with 8 copies of the TA repeat (1 copy more than reference). We deleted the representations that reported 7 copies and refreshed the database.

Links:

OMIM: 191740.0011; dbSNP: rs3064744

NCBI 1000 Genomes Browser:

rs3064744

Molecular consequence:

NM_001072.4:c.862-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_007120.3:c.868-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_019075.4:c.856-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_019076.5:c.856-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_019077.3:c.856-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_019078.2:c.868-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_019093.4:c.868-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_021027.3:c.856-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]
NM_205862.3:c.61-6800AT[8] - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

Decreased function

Observations:

202

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000597831	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	other (Feb 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001250152	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2024)	germline	clinical testing	Citation Link,
SCV001714671	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 12, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001723216	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16610035, 28520360, 7565971, 9435989, 11003624, 26467199, 11370628, 9639672, 28492532
SCV001915735	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Benign (Oct 2, 2019)	germline	clinical testing	Citation Link,
SCV002506315	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Nov 29, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	202	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Gilbert's syndrome: High frequency of the (TA)7 TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene.

Farheen S, Sengupta S, Santra A, Pal S, Dhali GK, Chakravorty M, Majumder PP, Chowdhury A.

World J Gastroenterol. 2006 Apr 14;12(14):2269-75.

PubMed [citation]

PMID:: 16610035
PMCID:: PMC4087660

See all PubMed Citations (10)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000597831.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001250152.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	202	not provided	not provided	clinical testing	not provided

Description

UGT1A1: PS3, PS4, PP4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		202	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714671.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001723216.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001915735.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002506315.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 4, 2025

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