The p.Pro229Gln variant in UGT1A1 has been reported in the heterogygous and compound heterozygous state in numerous individuals with Gilbert syndrome or Crigler-Najjar syndrome type II , however, most of them were also homozygous for other pathogenic variants in the gene. This variant has also been reported in ClinVar (Variation ID 12274). It has been identified in 1.9% (389/19954) of East Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Gagne 2002 PMID: 12181437, Udomuksorn 2007 PMID: 18004206); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, BS1_Supporting, BP4.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Conflicting interpretations of pathogenicity; other
Pathogenic(2); Uncertain significance(1); Benign(2)
- Review status:
- criteria provided, conflicting interpretations
- Submissions:
- 9 (Most recent: May 27, 2021)
- Last evaluated:
- Jul 9, 2020
- Accession:
- VCV000012274.18
- Variation ID:
- 12274
- Description:
- single nucleotide variant
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NM_000463.3(UGT1A1):c.686C>A (p.Pro229Gln)
- Allele ID
- 27313
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 2q37.1
- Genomic location
- 2: 233760973 (GRCh38) GRCh38 UCSC
- 2: 234669619 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000463.3:c.686C>A MANE Select NP_000454.1:p.Pro229Gln missense NM_001072.4:c.862-6061C>A MANE Select NM_007120.3:c.868-6061C>A MANE Select NM_019075.4:c.856-6061C>A MANE Select NM_019076.5:c.856-6061C>A MANE Select NM_019077.3:c.856-6061C>A MANE Select NM_019078.2:c.868-6061C>A MANE Select NM_019093.4:c.868-6061C>A MANE Select NM_021027.3:c.856-6061C>A MANE Select NM_205862.3:c.61-6061C>A NC_000002.12:g.233760973C>A NC_000002.11:g.234669619C>A NG_002601.2:g.176230C>A NG_033238.1:g.5701C>A LRG_733:g.5701C>A LRG_733t1:c.686C>A LRG_733p1:p.Pro229Gln P22309:p.Pro229Gln - Protein change
- P229Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:233760972:C:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- 0.00280 (A)
- Allele frequency
- 1000 Genomes Project 0.00280
- Trans-Omics for Precision Medicine (TOPMed) 0.00142
- Links
- ClinGen: CA122068
- UniProtKB: P22309#VAR_009505
- OMIM: 191740.0010
- dbSNP: rs35350960
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Conflicting interpretations of pathogenicity | 2 | criteria provided, conflicting interpretations | Jun 19, 2020 | RCV000147905.9 | |
| Conflicting interpretations of pathogenicity; other | 4 | criteria provided, conflicting interpretations | Jul 9, 2020 | RCV000299521.10 | |
| Pathogenic; Affects | 2 | no assertion criteria provided | May 1, 2019 | RCV000013062.27 | |
| Pathogenic | 1 | no assertion criteria provided | Dec 1, 2007 | RCV000013063.25 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| UGT1A | - | - | - | GRCh38 | - | 280 |
| UGT1A1 | - | - |
GRCh38 GRCh37 |
1 | 251 | |
| UGT1A10 | - | - |
GRCh38 GRCh37 |
- | 305 | |
| UGT1A3 | - | - |
GRCh38 GRCh37 |
- | 258 | |
| UGT1A4 | - | - |
GRCh38 GRCh37 |
- | 258 | |
| UGT1A5 | - | - |
GRCh38 GRCh37 |
- | 266 | |
| UGT1A6 | - | - |
GRCh38 GRCh37 |
- | 278 | |
| UGT1A7 | - | - |
GRCh38 GRCh37 |
- | 300 | |
| UGT1A8 | - | - |
GRCh38 GRCh37 |
1 | 307 | |
| UGT1A9 | - | - |
GRCh38 GRCh37 |
- | 303 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Benign
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000195396.1
Submitted: (Sep 11, 2014) |
|
|
|
other
(Sep 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins NTD LLC (GA)
Accession: SCV000344304.3
Submitted: (Sep 19, 2018) |
Number of individuals with the variant: 15
Zygosity: 1 Homozygote, 14 Single Heterozygote
Sex: mixed
|
|
|
Benign
(Dec 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001111446.2
Submitted: (Jan 29, 2020) |
|
|
|
Pathogenic
(Aug 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV001156826.2
Submitted: (Dec 11, 2020) |
|
|
|
Uncertain significance
(Jun 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine
Accession: SCV001653054.1
Submitted: (May 27, 2021) |
Comment:
The p.Pro229Gln variant in UGT1A1 has been reported in the heterogygous and compound heterozygous state in numerous individuals with Gilbert syndrome or Crigler-Najjar syndrome type … (more)
The p.Pro229Gln variant in UGT1A1 has been reported in the heterogygous and compound heterozygous state in numerous individuals with Gilbert syndrome or Crigler-Najjar syndrome type II , however, most of them were also homozygous for other pathogenic variants in the gene. This variant has also been reported in ClinVar (Variation ID 12274). It has been identified in 1.9% (389/19954) of East Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Gagne 2002 PMID: 12181437, Udomuksorn 2007 PMID: 18004206); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, BS1_Supporting, BP4. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories,Mayo Clinic
Accession: SCV001714674.1
Submitted: (May 26, 2021) |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 01, 2019)
|
no assertion criteria provided
Method: case-control
|
None
Affected status: unknown
Allele origin:
inherited
|
Difficult and Complicated Liver Diseases and Artificial Liver Center,Beijing You An Hospital, Capital Medical University
Accession: SCV001156254.1
Submitted: (Aug 07, 2019) |
Number of individuals with the variant: 13
Age: 25-55 years
Sex: mixed
Ethnicity/Population group: Chinese
|
|
|
Affects
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
GILBERT SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033308.2
Submitted: (Dec 30, 2010) |
Comment on evidence:
This variant has been designated UGT1A1*27 (Mackenzie et al., 1997). In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome (143500), Koiwai et … (more)
This variant has been designated UGT1A1*27 (Mackenzie et al., 1997). In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome (143500), Koiwai et al. (1995) identified a heterozygous 686C-A transversion in the UGT1A gene, resulting in a pro229-to-gln (P229Q) substitution. Expression studies in COS cells demonstrated approximately 14% of normal UGT activity, whereas enzymatic activity in the patient was approximately 30% of normal, suggesting a dominant-negative effect. Since, according to Peters et al. (1984), UGT exists as a tetramer on the luminal surface of the endoplasmic reticulum, the reduced level of UGT activity in the patient with Gilbert syndrome may be explained by the random formation of complexes of mutated UGT subunits and normally active UGT subunits on the endoplasmic reticulum. In a patient with Crigler-Najjar syndrome type II (606785), Yamamoto et al. (1998) identified a complex genotype consisting of heterozygosity for the P229Q mutation and homozygosity for a 2-bp insertion mutation (191740.0011). Udomuksorn et al. (2007) found that the P229Q mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 70% by increasing Km and decreasing Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate. (less)
|
|
|
Pathogenic
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
CRIGLER-NAJJAR SYNDROME, TYPE II
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033309.2
Submitted: (Dec 30, 2010) |
Comment on evidence:
This variant has been designated UGT1A1*27 (Mackenzie et al., 1997). In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome (143500), Koiwai et … (more)
This variant has been designated UGT1A1*27 (Mackenzie et al., 1997). In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome (143500), Koiwai et al. (1995) identified a heterozygous 686C-A transversion in the UGT1A gene, resulting in a pro229-to-gln (P229Q) substitution. Expression studies in COS cells demonstrated approximately 14% of normal UGT activity, whereas enzymatic activity in the patient was approximately 30% of normal, suggesting a dominant-negative effect. Since, according to Peters et al. (1984), UGT exists as a tetramer on the luminal surface of the endoplasmic reticulum, the reduced level of UGT activity in the patient with Gilbert syndrome may be explained by the random formation of complexes of mutated UGT subunits and normally active UGT subunits on the endoplasmic reticulum. In a patient with Crigler-Najjar syndrome type II (606785), Yamamoto et al. (1998) identified a complex genotype consisting of heterozygosity for the P229Q mutation and homozygosity for a 2-bp insertion mutation (191740.0011). Udomuksorn et al. (2007) found that the P229Q mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 70% by increasing Km and decreasing Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate. (less)
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of the <i>UGT1A1</i> Genotype in Hyperbilirubinemia Patients: Differences in Allele Frequency and Distribution. | Mi XX | BioMed research international | 2019 | PMID: 31467903 |
| UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children: A retrospective analysis and quantitative correlation. | Abuduxikuer K | Medicine | 2018 | PMID: 30544479 |
| Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type II. | Sun L | Medicine | 2017 | PMID: 29137095 |
| UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: a quantitative analysis. | Chen Z | Gene | 2014 | PMID: 25200497 |
| Mutation Analysis in Crigler-Najjar Syndrome Type II-Case Report and Literature Review. | Ranjan P | Journal of clinical and experimental hepatology | 2011 | PMID: 25755387 |
| 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 |
| 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 |
| Co-occurrence of three different mutations in the bilirubin UDP-glucuronosyltransferase gene in a Chinese family with Crigler-Najjar syndrome type I and Gilbert's syndrome. | Maruo Y | Clinical genetics | 2003 | PMID: 14616765 |
| Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). | Gagné JF | Molecular pharmacology | 2002 | PMID: 12181437 |
| Analysis of bilirubin uridine 5'-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II. | Yamamoto K | Journal of human genetics | 1998 | PMID: 9621515 |
| Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. | Koiwai O | Human molecular genetics | 1995 | PMID: 8528206 |
| Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. | Aono S | Lancet (London, England) | 1995 | PMID: 7715297 |
| The cDNA sequence and expression of a variant 17 beta-hydroxysteroid UDP-glucuronosyltransferase. | Mackenzie PI | The Journal of biological chemistry | 1990 | PMID: 1692835 |
| The molecular weights of UDP-glucuronyltransferase determined with radiation-inactivation analysis. A molecular model of bilirubin UDP-glucuronyltransferase. | Peters WH | The Journal of biological chemistry | 1984 | PMID: 6480579 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=UGT1A1 | - | - | - | - |
Text-mined citations for rs35350960...
HelpThese 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 May 07, 2022