Submissions for variant UGT1A1*6

gnomAD frequency: 0.00891  dbSNP: rs4148323

Total submissions: 20

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	2023-01-12	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
Neuberg Centre For Genomic Medicine, NCGM	RCV000022810	SCV005061043	pathogenic	Lucey-Driscoll syndrome		criteria provided, single submitter	clinical testing	The missense variant c.211G>A(p.Gly71Arg) in UGT1A1 gene has been reported in homozygous / compound heterozygous state in multiple individuals affected with UGT1A1 related disorders (Chen et. al., 2014; Iijima et. al., 2011). Experimental studies have shown that this missense change affects UGT1A1 function (Kouji Tagawaet. al., 2023; Sneitz et. al., 2010). The observed variant has allele frequency of 0.2% in gnomAD exomes database. This variant has been submitted to the ClinVar database Benign / Likely benign / Uncertain Significance / drug response / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Gly71Arg in UGT1A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 71 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000013071	SCV005061255	likely benign	Gilbert syndrome		criteria provided, single submitter	clinical testing	The missense variant c.211G>A (p.Gly71Arg) in the UGT1A1 gene has been reported previously in compound heterozygous and homozygous state in individuals affected with Gilbert's syndrome and Crigler-Najjar syndrome type II. Experimental studies have shown that this missense change affects UGT1A1 function (Gu et al., 2022; Sneitz et al., 2010; Yamamoto et al., 1998). This variant is reported with a high allele frequency in the gnomAD. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic/Uncertain significance/Likely benign/Benign. In a meta-analysis study, the result suggests that the p.Gly71Arg mutation of the UGT1A1 gene is a risk factor for developing neonatal hyperbilirubinemia in both Asians and Caucasian subjects (Mehrad-Majd et al., 2019). The amino acid Glycine at position 71 is changed to an Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gly71Arg in UGT1A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Benign.
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