ClinVar Miner

Submissions for variant UGT1A1*6

gnomAD frequency: 0.00891  dbSNP: rs4148323
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000173139 SCV000224228 likely benign not specified 2014-07-03 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000173139 SCV000304405 benign not specified criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000013071 SCV000428642 likely benign Gilbert syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000013071 SCV000538072 likely pathogenic Gilbert syndrome 2016-03-30 criteria provided, single submitter clinical testing The c.211G>A (p.Gly71Arg) missense variant in the UGT1A1 gene is a known common variant associated with Gilbert Syndrome and hyperbilirubinemia in individuals of East Asian descent. Numerous case-control studies have demonstrated this variant is significantly prevalent in affected individuals relative to unaffected controls (Fu and Liu, 2005; Lin et al., 2009; Zhou et al., 2009; Prachukthum et al., 2009; Gao et al., 2010; Long et al., 2011a; Long et al., 2011b; Chen et al., 2014). Multiple in vitro studies have shown that this variant leads to reduced enzymatic activity, and this variant is associated with elevated serum bilirubin in infants (Yamamoto et al., 1998; Sneitz et al., 2010; Chou et al., 2011). The allele frequency is high in the population databases for individuals of East Asian descent, which is expected given the high prevalence of the disease (1000 Genomes = 13.8% [EAS]; ExAC = 15.24% [EAS]). Hence, a yet unknown genetic modifier that is specific to the East Asian population may contribute to the high disease prevalence. Finally, a reputable clinical diagnostic laboratory has reported this variant as Likely Pathogenic (University of Chicago). Together, this collective evidence supports the classification of the c.211G>A (p.Gly71Arg) as a Likely Pathogenic variant for Gilbert Syndrome.
Medical Genetics Summaries RCV000664403 SCV000788335 drug response Irinotecan response 2018-04-04 criteria provided, single submitter curation UGT1A1*6 appears to be an important predictor of severe toxicity to irinotecan therapy in Asian populations. In Japan, a reduced dose of irinotecan is recommended for individuals with UGT1A1 *6/*6, *6/*28, and *28/*28 genotypes.
Mendelics RCV000987059 SCV001136249 likely pathogenic Crigler-Najjar syndrome, type II 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001508487 SCV001157259 pathogenic not provided 2022-11-21 criteria provided, single submitter clinical testing The UGT1A1 c.211G>A; p.Gly71Arg variant, also known as the *6 allele, is associated with an increased incidence of neonatal hyperbilirubinemia (Akaba 1999, Maruo 2000), and when homozygous, causes Gilbert syndrome (Takeuchi 2004). Functional analyses of the variant protein show decreased maximum enzyme activity (Udomuksorn 2007). This variant is found predominantly in the East Asian population with an overall frequency of 15.3% (3053/19950 alleles, including 250 homozygotes) in the Genome Aggregation Database. One study also suggests that neonates with the UGT1A1*6 allele experiencing a greater than 5% weight loss in the first 72 hours after birth have a higher incidence of hyperbilirubinemia (Sato 2013). Furthermore, when homozygous or in combination with other UGT1A1 promoter variants (e.g., greater than 6 TA repeats), this variant may predict an increased risk of irinotecan-related neutropenia (Barbarino 2014, Han 2014). There is currently insufficient evidence regarding the clinical impact of the *6 allele in patients treated with atazanavir (Gammal 2016, Park 2010). Based on available information, this variant is classified as a mildly pathogenic variant. References: Akaba K et al. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet. 1999;44(1):22-5. PMID: 9929972 Barbarino JM et al. PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genomics. Pharmacogenet Genomics. 2014 Mar;24(3):177-83. PMID: 24492252 Gammal RS et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 Apr;99(4):363-9. PMID: 26417955 Han FF et al. Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patientsCancer Chemother Pharmacol. 2014 Apr;73(4):779-88. PMID: 24519753 Maruo Y et al. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene. Pediatrics. 2000 Nov;106(5):E59. PMID: 11061796 Park WB et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. Clin Infect Dis. 2010 Jul 1;51(1):101-6. PMID: 20504240 Sato H et al. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding. J Hum Genet. 2013 Jan;58(1):7-10. PMID: 23014115 Takeuchi K et al. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol. 2004 Sep;19(9):1023-8. PMID: 15304120 Udomuksorn W et al. Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet Genomics. 2007 Dec. PMID: 18004206
Mayo Clinic Laboratories, Mayo Clinic RCV001508487 SCV001714673 pathogenic not provided 2022-12-28 criteria provided, single submitter clinical testing
Invitae RCV001508487 SCV001728288 pathogenic not provided 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 71 of the UGT1A1 protein (p.Gly71Arg). This variant is present in population databases (rs4148323, gnomAD 15%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with UGT1A1-related hyperbilirubinemia. Homozygous individuals for this variant present with Gilbert syndrome (PMID: 19397531, 20975617, 21272068, 21342357, 25200497, 11061796). In some cases this variant has been reported to occur on the same chromosome (in cis) with p.Tyr486Asp, forming a haplotype. Homozygous individuals for this haplotype present with Crigler-Najjar syndrome type II (PMID: 9630669, 21319362, 15304120). This variant is also known as UGT1A1*6. ClinVar contains an entry for this variant (Variation ID: 12280). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UGT1A1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 9630669, 19830808). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001508487 SCV001832894 pathogenic not provided 2022-09-15 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with reduced UGTA1A protein activity, especially when the variant is in the homozygous state or in the presence of additional UGT1A1 pathogenic variants (Yamamoto K et al., 1998; Sneitz N et al., 2010; Gagn JF et al., 2002; Tagawa K et al., 2022); Also known as UGT1A1*6; This variant is associated with the following publications: (PMID: 31207142, 29607327, 20975617, 25967674, 20504240, 23014115, 25200497, 24615032, 23388413, 25262004, 19243019, 23875061, 26716871, 21342357, 20528217, 19325249, 20924216, 24749086, 22046580, 21319362, 21092520, 7715297, 34007799, 16255851, 29115431, 19397531, 17850628, 21272068, 28100328, 31122244, 29179591, 30298137, 9621515, 30669781, 34074250, 31737051, 32287101, 32762156, 24448639, 11316168, 24519753, 29534743, 12502904, 27895797, 24308720, 35131284, 28585035, 26830078, 28520360, 24033692, 27220761, 18004206, 19390945, 26857783, 26604633, 11061796, 10472535, 9929972, 26417955, 24492252, 19830808, 12181437, 9784835, 16610035, 25087612, 35930428, 9630669, 8280139, 21297505, 27323053, 29137095, 15304120, 10412811)
CeGaT Center for Human Genetics Tuebingen RCV001508487 SCV002563665 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001508487 SCV002817237 uncertain significance not provided 2021-01-20 criteria provided, single submitter clinical testing This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000173139 SCV004024686 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
OMIM RCV000013071 SCV000033317 affects Gilbert syndrome 2013-01-01 no assertion criteria provided literature only
OMIM RCV000022810 SCV000044099 pathogenic Lucey-Driscoll syndrome 2013-01-01 no assertion criteria provided literature only
OMIM RCV000022811 SCV000044100 association Bilirubin, serum level of, quantitative trait locus 1 2013-01-01 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000013071 SCV000249368 other Gilbert syndrome 2016-01-25 no assertion criteria provided clinical testing
Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University RCV000013071 SCV001156253 pathogenic Gilbert syndrome 2019-05-01 no assertion criteria provided case-control

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