VCV000012280.54 - ClinVar

UGT1A1*6

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity; drug response
Pathogenic(6); Likely pathogenic(2); Uncertain significance(2); Benign(1); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

UGT1A1*6

Variation ID: 12280 Accession: VCV000012280.54

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.1 2: 233760498 (GRCh38) [ NCBI UCSC ] 2: 234669144 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000463.3:c.211G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000454.1:p.Gly71Arg	missense
NM_001072.4:c.862-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_007120.3:c.868-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019075.4:c.856-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019076.5:c.856-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019077.3:c.856-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019078.2:c.868-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019093.4:c.868-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_021027.3:c.856-6536G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_205862.3:c.61-6536G>A		intron variant
NC_000002.12:g.233760498G>A
NC_000002.11:g.234669144G>A
NG_002601.2:g.175755G>A
NG_033238.1:g.5226G>A
LRG_733:g.5226G>A
LRG_733t1:c.211G>A	LRG_733p1:p.Gly71Arg

... more HGVS ... less HGVS

Protein change

G71R

Other names

NM_000463.2(UGT1A1):c.211G>A (p.Gly71Arg)
211G>A

Canonical SPDI

NC_000002.12:233760497:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Decreased function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.03435 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.03186

1000 Genomes Project 0.03435

Trans-Omics for Precision Medicine (TOPMed) 0.01002

Exome Aggregation Consortium (ExAC) 0.02066

The Genome Aggregation Database (gnomAD), exomes 0.02235

The Genome Aggregation Database (gnomAD) 0.00891

Links

Genetic Testing Registry (GTR): GTR000613302 OMIM: 191740.0016 dbSNP: rs4148323 PharmGKB Clinical Annotation: 981201713 PharmGKB Clinical Annotation: 982047955 ClinGen: CA122078 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
UGT1A	-	-	-	GRCh38	-	589
UGT1A1		-	-	GRCh38 GRCh37	2	373
UGT1A10		-	-	GRCh38 GRCh37	-	591
UGT1A3		-	-	GRCh38 GRCh37	-	397
UGT1A4		-	-	GRCh38 GRCh37	-	423
UGT1A5		-	-	GRCh38 GRCh37	-	441
UGT1A6		-	-	GRCh38 GRCh37	-	484
UGT1A7		-	-	GRCh38 GRCh37	-	536
UGT1A8		-	-	GRCh38 GRCh37	-	619
UGT1A9		-	-	GRCh38 GRCh37	-	571

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Gilbert syndrome	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Apr 27, 2017	RCV000013071.55
Bilirubin, serum level of, quantitative trait locus 1	association (1)	no assertion criteria provided	Jan 1, 2013	RCV000022811.10
Lucey-Driscoll syndrome	Pathogenic (2)	criteria provided, single submitter	-	RCV000022810.33
not specified	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Aug 15, 2023	RCV000173139.23
Irinotecan response	drug response (1)	criteria provided, single submitter	Apr 4, 2018	RCV000664403.10
Crigler-Najjar syndrome, type II	Likely pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000987059.9
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jan 25, 2024	RCV001508487.44

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304405.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely pathogenic (Mar 30, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gilbert syndrome Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000538072.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Comment: 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 … (more) 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. (less)
drug response (Apr 04, 2018)	criteria provided, single submitter (Medical Genetics Summaries: Irinotecan therapy and UGT1A1 genotype) Method: curation	Irinotecan response Affected status: yes Allele origin: germline	Medical Genetics Summaries Accession: SCV000788335.1 First in ClinVar: Jul 29, 2018 Last updated: Jul 29, 2018	Publications: PubMed (7) PubMed: 28520360‚ 26830078‚ 26857783‚ 27220761‚ 26604633‚ 28585035‚ 24033692 pmc: 5104260 pmc: 5104260 Other databases https://dailymed.nlm.nih.gov/dai… https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d04f2471-3085-4fc8-a657-bb3918d48e6eu http://kennisbank.knmp.nl http://kennisbank.knmp.nl http://www.cdc.gov/genomics/gtes… http://www.cdc.gov/genomics/gtesting/EGAPP/recommend/UGT1A1.htm Comment: UGT1A16 appears to be an important predictor of severe toxicity to irinotecan therapy in Asian populations. In Japan, a reduced dose of irinotecan is recommended … (more) UGT1A16 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. (less)
Uncertain significance (Jan 20, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002817237.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: 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.
Pathogenic (Nov 21, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157259.4 First in ClinVar: Feb 10, 2020 Last updated: Mar 04, 2023	Comment: 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 … (more) 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 UGT1A16 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 UGT1A16 or UGT1A16/28 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 1A128 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 (less)
Pathogenic (Sep 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001832894.3 First in ClinVar: Sep 10, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lucey-Driscoll syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005061043.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: 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 … (more) 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. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gilbert syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005061255.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: 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 … (more) 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. (less) Clinical Features: Abnormality of the liver (present)
Likely benign (Jul 03, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224228.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=UGT1A1 Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Crigler-Najjar syndrome, type II Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136249.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Gilbert syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000428642.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 15304120‚ 17850628‚ 12502904 Comment: 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, … (more) 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. (less)
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004024686.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001728288.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 19397531‚ 20975617‚ 21272068‚ 21342357‚ 25200497‚ 11061796‚ 9630669‚ 21319362‚ 15304120‚ 19830808 Comment: 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). … (more) 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. (less)
Pathogenic (Jan 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714673.4 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Publications: PubMed (4) PubMed: 9630669‚ 15304120‚ 9784835‚ 19390945 Number of individuals with the variant: 53
Pathogenic (Jun 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002563665.16 First in ClinVar: Aug 23, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jan 01, 2013)	no assertion criteria provided Method: literature only	HYPERBILIRUBINEMIA, TRANSIENT FAMILIAL NEONATAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044099.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (8) PubMed: 10412811‚ 9784835‚ 9929972‚ 10472535‚ 11061796‚ 18004206‚ 19243019‚ 23014115 Comment on evidence: This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous … (more) This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous 211G-A transition in exon 1 of the UGT1A1 gene, resulting in a gly71-to-arg substitution (G71R). The parents were heterozygous for the mutation. Akaba et al. (1998) reported that the G71R mutation of the UGT1A1 gene, which in homozygous state causes Gilbert syndrome, is prevalent among Japanese, Korean, and Chinese populations, with a gene frequency of 0.13, 0.23, and 0.23, respectively. Akaba et al. (1999) showed that neonates carrying the G71R mutation have significantly increased bilirubin levels (237900) at days 2 to 4 in a gene dose-dependent manner and that the frequency of this mutation was significantly higher in the neonates who required phototherapy than in those who did not. They suggested that the G71R mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese. Among 20 children with acute leukemia, Kimura et al. (1999) found 4 with intermittent unconjugated hyperbilirubinemia during the course of combined chemotherapy. The G71R mutation was detected in the 4 patients with hyperbilirubinemia but was not found in the other 16 patients. Two of the 4 were heterozygotes; one was a homozygote for the G71R mutation; and the other was a compound heterozygote for G71R and the TA insertion mutation in the TATA box (191740.0011). Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Thus the infants had transient familial neonatal hyperbilirubinemia (237900). Sequencing of the UGT1A1 gene revealed that 8 infants were homozygous and 7 heterozygous for the G71R mutation. Another UGT1A1 missense mutation (191740.0017) was found in one of the G71R homozygotes, and an insertion in the TATA box of UGT1A1 (191740.0011) was found in one of the G71R heterozygotes. Udomuksorn et al. (2007) found that the G71R mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 50% via a reduction in Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism (191740.0011) and rs4148323 (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the A allele of rs4148323 for the Han, Uygur, and Kazakh populations was 0.211, 0.168, and 0.211, respectively, and could explain 9.8%, 4.5%, and 3.9%, respectively, of the total variation in bilirubin levels, Sato et al. (2013) found that 56 (14%) of 401 Japanese neonates who were exclusively breastfed developed hyperbilirubinemia and required phototherapy. Neonates with a 10% or greater loss of body weight since birth had a significantly higher peak bilirubin level and incidence of hyperbilirubinemia, higher frequency of cesarean delivery, and shorter gestational period compared to those with less than 10% loss of body weight. Sex and body weight at birth were not significantly different between the 2 groups. UGT1A1 genotyping of the entire cohort showed that the frequency of the G71R polymorphism was 0.18 and was higher in neonates with body weight loss less than 10%. However, maximal body weight loss during the neonatal period was the only independent risk factor for the development of neonatal hyperbilirubinemia (odds ratio of 1.25). Although presence of the G71R variant was not a significant independent risk factor for neonatal hyperbilirubinemia overall, subgroup analysis revealed that G71R was a risk factor only in neonates with a 5% or greater maximal body weight loss, and the influence correlated with the degree of body weight loss. Sato et al. (2013) suggested that adequate feeding in the neonatal period may overcome the genetic predisposing factor of G71R to neonatal hyperbilirubinemia. (less)
association (Jan 01, 2013)	no assertion criteria provided Method: literature only	BILIRUBIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044100.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (8) PubMed: 10412811‚ 9784835‚ 9929972‚ 10472535‚ 11061796‚ 18004206‚ 19243019‚ 23014115 Comment on evidence: This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous … (more) This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous 211G-A transition in exon 1 of the UGT1A1 gene, resulting in a gly71-to-arg substitution (G71R). The parents were heterozygous for the mutation. Akaba et al. (1998) reported that the G71R mutation of the UGT1A1 gene, which in homozygous state causes Gilbert syndrome, is prevalent among Japanese, Korean, and Chinese populations, with a gene frequency of 0.13, 0.23, and 0.23, respectively. Akaba et al. (1999) showed that neonates carrying the G71R mutation have significantly increased bilirubin levels (237900) at days 2 to 4 in a gene dose-dependent manner and that the frequency of this mutation was significantly higher in the neonates who required phototherapy than in those who did not. They suggested that the G71R mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese. Among 20 children with acute leukemia, Kimura et al. (1999) found 4 with intermittent unconjugated hyperbilirubinemia during the course of combined chemotherapy. The G71R mutation was detected in the 4 patients with hyperbilirubinemia but was not found in the other 16 patients. Two of the 4 were heterozygotes; one was a homozygote for the G71R mutation; and the other was a compound heterozygote for G71R and the TA insertion mutation in the TATA box (191740.0011). Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Thus the infants had transient familial neonatal hyperbilirubinemia (237900). Sequencing of the UGT1A1 gene revealed that 8 infants were homozygous and 7 heterozygous for the G71R mutation. Another UGT1A1 missense mutation (191740.0017) was found in one of the G71R homozygotes, and an insertion in the TATA box of UGT1A1 (191740.0011) was found in one of the G71R heterozygotes. Udomuksorn et al. (2007) found that the G71R mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 50% via a reduction in Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism (191740.0011) and rs4148323 (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the A allele of rs4148323 for the Han, Uygur, and Kazakh populations was 0.211, 0.168, and 0.211, respectively, and could explain 9.8%, 4.5%, and 3.9%, respectively, of the total variation in bilirubin levels, Sato et al. (2013) found that 56 (14%) of 401 Japanese neonates who were exclusively breastfed developed hyperbilirubinemia and required phototherapy. Neonates with a 10% or greater loss of body weight since birth had a significantly higher peak bilirubin level and incidence of hyperbilirubinemia, higher frequency of cesarean delivery, and shorter gestational period compared to those with less than 10% loss of body weight. Sex and body weight at birth were not significantly different between the 2 groups. UGT1A1 genotyping of the entire cohort showed that the frequency of the G71R polymorphism was 0.18 and was higher in neonates with body weight loss less than 10%. However, maximal body weight loss during the neonatal period was the only independent risk factor for the development of neonatal hyperbilirubinemia (odds ratio of 1.25). Although presence of the G71R variant was not a significant independent risk factor for neonatal hyperbilirubinemia overall, subgroup analysis revealed that G71R was a risk factor only in neonates with a 5% or greater maximal body weight loss, and the influence correlated with the degree of body weight loss. Sato et al. (2013) suggested that adequate feeding in the neonatal period may overcome the genetic predisposing factor of G71R to neonatal hyperbilirubinemia. (less)
Affects (Jan 01, 2013)	no assertion criteria provided Method: literature only	GILBERT SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033317.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (8) PubMed: 10412811‚ 9784835‚ 9929972‚ 10472535‚ 11061796‚ 18004206‚ 19243019‚ 23014115 Comment on evidence: This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous … (more) This variant is designated UGT1A16 and rs4148323. In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous 211G-A transition in exon 1 of the UGT1A1 gene, resulting in a gly71-to-arg substitution (G71R). The parents were heterozygous for the mutation. Akaba et al. (1998) reported that the G71R mutation of the UGT1A1 gene, which in homozygous state causes Gilbert syndrome, is prevalent among Japanese, Korean, and Chinese populations, with a gene frequency of 0.13, 0.23, and 0.23, respectively. Akaba et al. (1999) showed that neonates carrying the G71R mutation have significantly increased bilirubin levels (237900) at days 2 to 4 in a gene dose-dependent manner and that the frequency of this mutation was significantly higher in the neonates who required phototherapy than in those who did not. They suggested that the G71R mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese. Among 20 children with acute leukemia, Kimura et al. (1999) found 4 with intermittent unconjugated hyperbilirubinemia during the course of combined chemotherapy. The G71R mutation was detected in the 4 patients with hyperbilirubinemia but was not found in the other 16 patients. Two of the 4 were heterozygotes; one was a homozygote for the G71R mutation; and the other was a compound heterozygote for G71R and the TA insertion mutation in the TATA box (191740.0011). Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Thus the infants had transient familial neonatal hyperbilirubinemia (237900). Sequencing of the UGT1A1 gene revealed that 8 infants were homozygous and 7 heterozygous for the G71R mutation. Another UGT1A1 missense mutation (191740.0017) was found in one of the G71R homozygotes, and an insertion in the TATA box of UGT1A1 (191740.0011) was found in one of the G71R heterozygotes. Udomuksorn et al. (2007) found that the G71R mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 50% via a reduction in Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism (191740.0011) and rs4148323 (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the A allele of rs4148323 for the Han, Uygur, and Kazakh populations was 0.211, 0.168, and 0.211, respectively, and could explain 9.8%, 4.5%, and 3.9%, respectively, of the total variation in bilirubin levels, Sato et al. (2013) found that 56 (14%) of 401 Japanese neonates who were exclusively breastfed developed hyperbilirubinemia and required phototherapy. Neonates with a 10% or greater loss of body weight since birth had a significantly higher peak bilirubin level and incidence of hyperbilirubinemia, higher frequency of cesarean delivery, and shorter gestational period compared to those with less than 10% loss of body weight. Sex and body weight at birth were not significantly different between the 2 groups. UGT1A1 genotyping of the entire cohort showed that the frequency of the G71R polymorphism was 0.18 and was higher in neonates with body weight loss less than 10%. However, maximal body weight loss during the neonatal period was the only independent risk factor for the development of neonatal hyperbilirubinemia (odds ratio of 1.25). Although presence of the G71R variant was not a significant independent risk factor for neonatal hyperbilirubinemia overall, subgroup analysis revealed that G71R was a risk factor only in neonates with a 5% or greater maximal body weight loss, and the influence correlated with the degree of body weight loss. Sato et al. (2013) suggested that adequate feeding in the neonatal period may overcome the genetic predisposing factor of G71R to neonatal hyperbilirubinemia. (less)
other (Jan 25, 2016)	no assertion criteria provided Method: clinical testing	Gilbert syndrome Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000249368.2 First in ClinVar: Oct 05, 2015 Last updated: Nov 10, 2017
Pathogenic (May 01, 2019)	no assertion criteria provided Method: case-control	Gilbert syndrome Affected status: yes Allele origin: inherited	Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University Accession: SCV001156253.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Number of individuals with the variant: 120 Age: 25-55 years Sex: mixed Ethnicity/Population group: Chinese
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Comment:

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.

Comment:

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

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Decreased function			Medical Genetics Summaries Accession: SCV000788335.1	Publications PubMed (7) pmc: 5104260 Other databases https://dailymed.nlm.nih.gov/dai… http://kennisbank.knmp.nl http://www.cdc.gov/genomics/gtes…

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis.	Zhang X	Cancer chemotherapy and pharmacology	2017	PMID: 28585035
UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.	Cui C	Oncology letters	2016	PMC5104260
UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer.	Xu C	Cancer chemotherapy and pharmacology	2016	PMID: 27220761
Effects of UGT1A16, UGT1A128, and ABCB1-3435C>T polymorphisms on irinotecan induced toxicity in Chinese cancer patients.	Yan L	International journal of clinical pharmacology and therapeutics	2016	PMID: 26857783
Correlation of UGT1A1()28 and ()6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients.	Atasilp C	Drug metabolism and pharmacokinetics	2016	PMID: 26830078
Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer.	Fujita K	World journal of gastroenterology	2015	PMID: 26604633
UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: a quantitative analysis.	Chen Z	Gene	2014	PMID: 25200497
UGT1A16, 1A73, and 1A9*22 genotypes predict severe neutropenia in FOLFIRI-treated metastatic colorectal cancer in two prospective studies in Japan.	Hazama S	Cancer science	2013	PMID: 24033692
Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding.	Sato H	Journal of human genetics	2013	PMID: 23014115
Association of neonatal hyperbilirubinemia with uridine diphosphate-glucuronosyltransferase 1A1 gene polymorphisms: meta-analysis.	Long J	Pediatrics international : official journal of the Japan Pediatric Society	2011	PMID: 21342357
Hereditary spherocytosis coexisting with UDP-glucuronosyltransferase deficiency highly suggestive of Crigler-Najjar syndrome type II.	Iijima S	Yonsei medical journal	2011	PMID: 21319362
Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence.	Long J	Acta paediatrica (Oslo, Norway : 1992)	2011	PMID: 21272068
211 G to a variation of UDP-glucuronosyl transferase 1A1 gene and neonatal breastfeeding jaundice.	Chou HC	Pediatric research	2011	PMID: 20975617
Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants.	Sneitz N	Human mutation	2010	PMID: 19830808
Genetic polymorphisms in Thai neonates with hyperbilirubinemia.	Prachukthum S	Acta paediatrica (Oslo, Norway : 1992)	2009	PMID: 19397531
UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.	Onoue M	International journal of clinical oncology	2009	PMID: 19390945
Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations.	Lin R	Human mutation	2009	PMID: 19243019
Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates.	Udomuksorn W	Pharmacogenetics and genomics	2007	PMID: 18004206
Combined UGT1A1 and UGT1A7 variant alleles are associated with increased risk of Gilbert's syndrome in Taiwanese adults.	Teng HC	Clinical genetics	2007	PMID: 17850628
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.	Takeuchi K	Journal of gastroenterology and hepatology	2004	PMID: 15304120
Gly71Arg mutation of the bilirubin UDP-glucuronosyltransferase 1A1 gene is associated with neonatal hyperbilirubinemia in the Japanese population.	Yamamoto A	The Kobe journal of medical sciences	2002	PMID: 12502904
Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene.	Maruo Y	Pediatrics	2000	PMID: 11061796
Intermittent jaundice in patients with acute leukaemia: a common mutation of the bilirubin uridine-diphosphate glucuronosyltransferase gene among Asians.	Kimura T	Journal of inherited metabolic disease	1999	PMID: 10472535
A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a mutation in the bilirubin UDP-glucuronosyltransferase gene.	Maruo Y	European journal of pediatrics	1999	PMID: 10412811
Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese.	Akaba K	Journal of human genetics	1999	PMID: 9929972
Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese.	Akaba K	Biochemistry and molecular biology international	1998	PMID: 9784835
Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler-Najjar syndrome type II.	Yamamoto K	Biochimica et biophysica acta	1998	PMID: 9630669
http://www.cdc.gov/genomics/gtesting/EGAPP/recommend/UGT1A1.htm	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=UGT1A1	-	-	-	-
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d04f2471-3085-4fc8-a657-bb3918d48e6eu	-	-	-	-
Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines, HLA: allopurinol	-	-	-	-
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Text-mined citations for rs4148323 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

UGT1A1*6

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs4148323 ...