UGT1A1*6 AND Gilbert syndrome
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000013071.54
Allele description [Variation Report for UGT1A1*6]
UGT1A1*6
- Genes:
- UGT1A:UDP glucuronosyltransferase family 1 member A complex locus [Gene - HGNC]
- UGT1A10:UDP glucuronosyltransferase family 1 member A10 [Gene - OMIM - HGNC]
- UGT1A1:UDP glucuronosyltransferase family 1 member A1 [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:
- single nucleotide variant
- Cytogenetic location:
- 2q37.1
- Genomic location:
- Preferred name:
- UGT1A1*6
- Other names:
- NM_000463.2(UGT1A1):c.211G>A (p.Gly71Arg); 211G>A
- HGVS:
- NC_000002.12:g.233760498G>A
- NG_002601.2:g.175755G>A
- NG_033238.1:g.5226G>A
- NM_000463.3:c.211G>AMANE SELECT
- NM_001072.4:c.862-6536G>AMANE SELECT
- NM_007120.3:c.868-6536G>AMANE SELECT
- NM_019075.4:c.856-6536G>AMANE SELECT
- NM_019076.5:c.856-6536G>AMANE SELECT
- NM_019077.3:c.856-6536G>AMANE SELECT
- NM_019078.2:c.868-6536G>AMANE SELECT
- NM_019093.4:c.868-6536G>AMANE SELECT
- NM_021027.3:c.856-6536G>AMANE SELECT
- NM_205862.3:c.61-6536G>A
- NP_000454.1:p.Gly71Arg
- NP_000454.1:p.Gly71Arg
- LRG_733t1:c.211G>A
- LRG_733:g.5226G>A
- LRG_733p1:p.Gly71Arg
- NC_000002.11:g.234669144G>A
- NM_000463.2:c.211G>A
This HGVS expression did not pass validation- Protein change:
- G71R; Gly71Arg
- Links:
- Genetic Testing Registry (GTR): GTR000613302; Medical Genetics Summaries: UGT1A1*6; PharmGKB Clinical Annotation: 981201713; PharmGKB Clinical Annotation: 982047955; OMIM: 191740.0016; dbSNP: rs4148323
- NCBI 1000 Genomes Browser:
- rs4148323
- Molecular consequence:
- NM_001072.4:c.862-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_007120.3:c.868-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_019075.4:c.856-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_019076.5:c.856-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_019077.3:c.856-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_019078.2:c.868-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_019093.4:c.868-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_021027.3:c.856-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_205862.3:c.61-6536G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_000463.3:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]
- Functional consequence:
- Decreased function
Condition(s)
- Name:
- Gilbert syndrome
- Synonyms:
- HYPERBILIRUBINEMIA I; HYPERBILIRUBINEMIA, ARIAS TYPE; Gilbert Disease; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0007745; MedGen: C0017551; OMIM: 143500
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000033317 | OMIM | no assertion criteria provided | Affects (Jan 1, 2013) | germline | literature only | |
SCV000249368 | Genetic Services Laboratory, University of Chicago | no assertion criteria provided | other (Jan 25, 2016) | germline | clinical testing | |
SCV000428642 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) | Likely benign (Apr 27, 2017) | germline | clinical testing | |
SCV000538072 | Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 30, 2016) | germline | clinical testing | |
SCV001156253 | Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University | no assertion criteria provided | Pathogenic (May 1, 2019) | inherited | case-control | |
SCV005061255 | Neuberg Centre For Genomic Medicine, NCGM | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely benign | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | not provided | 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 |
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
Chinese | inherited | yes | 120 | not provided | not provided | not provided | not provided | case-control |
Citations
PubMed
Maruo Y, Wada S, Yamamoto K, Sato H, Yamano T, Shimada M.
Eur J Pediatr. 1999 Jul;158(7):547-9.
- PMID:
- 10412811
Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, Umeda H, Yoshida H, Umetsu K, Chiba H, Yuasa I, Hayasaka K.
Biochem Mol Biol Int. 1998 Sep;46(1):21-6.
- PMID:
- 9784835
Details of each submission
From OMIM, SCV000033317.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (8) |
Description
This variant is designated UGT1A1*6 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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Genetic Services Laboratory, University of Chicago, SCV000249368.2
# | 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 | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Illumina Laboratory Services, Illumina, SCV000428642.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
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.
# | 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 Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538072.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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.
# | 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 Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University, SCV001156253.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | Chinese | 120 | not provided | not provided | case-control | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | inherited | yes | not provided | not provided | not provided | 120 | not provided | not provided | not provided |
From Neuberg Centre For Genomic Medicine, NCGM, SCV005061255.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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.
# | 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 |
Last Updated: Aug 25, 2024