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NM_000463.3(UGT1A1):c.686C>A (p.Pro229Gln) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity; other (4 submissions)
Last evaluated:
Jan 18, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000299521.32

Allele description [Variation Report for NM_000463.3(UGT1A1):c.686C>A (p.Pro229Gln)]

NM_000463.3(UGT1A1):c.686C>A (p.Pro229Gln)

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:
NM_000463.3(UGT1A1):c.686C>A (p.Pro229Gln)
HGVS:
  • NC_000002.12:g.233760973C>A
  • NG_002601.2:g.176230C>A
  • NG_033238.1:g.5701C>A
  • NM_000463.3:c.686C>AMANE SELECT
  • NM_001072.4:c.862-6061C>AMANE SELECT
  • NM_007120.3:c.868-6061C>AMANE SELECT
  • NM_019075.4:c.856-6061C>AMANE SELECT
  • NM_019076.5:c.856-6061C>AMANE SELECT
  • NM_019077.3:c.856-6061C>AMANE SELECT
  • NM_019078.2:c.868-6061C>AMANE SELECT
  • NM_019093.4:c.868-6061C>AMANE SELECT
  • NM_021027.3:c.856-6061C>AMANE SELECT
  • NM_205862.3:c.61-6061C>A
  • NP_000454.1:p.Pro229Gln
  • NP_000454.1:p.Pro229Gln
  • LRG_733t1:c.686C>A
  • LRG_733:g.5701C>A
  • LRG_733p1:p.Pro229Gln
  • NC_000002.11:g.234669619C>A
  • NM_000463.2:c.686C>A
  • P22309:p.Pro229Gln
Protein change:
P229Q; PRO229GLN
Links:
UniProtKB: P22309#VAR_009505; OMIM: 191740.0010; dbSNP: rs35350960
NCBI 1000 Genomes Browser:
rs35350960
Molecular consequence:
  • NM_001072.4:c.862-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007120.3:c.868-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_019075.4:c.856-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_019076.5:c.856-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_019077.3:c.856-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_019078.2:c.868-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_019093.4:c.868-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_021027.3:c.856-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_205862.3:c.61-6061C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000463.3:c.686C>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
16

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000344304Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)		other
(Sep 17, 2018) 		germlineclinical testing

Citation Link,

SCV001111446Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 18, 2024) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001156826ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)		Pathogenic
(Oct 26, 2023) 		germlineclinical testing

Citation Link,

SCV001714674Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jul 9, 2020) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown16not providednot providednot providednot providedclinical testing

Citations

PubMed

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, Poon KK, Ito M, Iwai M, Takahashi H, Mori A, Sato H, Takeuchi Y.

Clin Genet. 2003 Nov;64(5):420-3.

PubMed [citation]
PMID:
14616765

Correlation of mutational analysis to clinical features in Taiwanese patients with Gilbert's syndrome.

Hsieh SY, Wu YH, Lin DY, Chu CM, Wu M, Liaw YF.

Am J Gastroenterol. 2001 Apr;96(4):1188-93.

PubMed [citation]
PMID:
11316168
See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000344304.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided15not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided15not providednot providednot provided

From Invitae, SCV001111446.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 229 of the UGT1A1 protein (p.Pro229Gln). This variant is present in population databases (rs35350960, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with Gilbert disease (PMID: 7715297, 8528206, 14616765). This variant is frequently observed to be in cis with the c.-41_-40dup (aka UGT1A1*28 or (TA)7) variant (PMID: 11316168, 19325249, 15304120) This variant is also known as UGT1A1*27. ClinVar contains an entry for this variant (Variation ID: 12274). 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: 8528206, 18004206). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156826.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The UGT1A1 c.686C>A, p.Pro229Gln variant (rs35350960; ClinVar Variation ID: 12274), also known as the UGT1A1*27 allele (Mackenzie 1997), is reported in the literature in individuals of East Asian descent affected with Gilbert syndrome, almost always with one or two copies of the pathogenic-mild UGT1A1 *28 promoter variant (Huang 2000, Koiwai 1995, Maruo 2003, Sai 2004, Sun 2017). Functional analyses of the p.Pro229Gln variant protein showed markedly reduced enzyme activity (Koiwai 1995, Udomuksorn 2007). Individuals heterozygous for the UGT1A1*27 allele may also be at increased risk for drug toxicity when treated with irinotecan (Ando 2000, Teh 2012). This variant is found predominantly in the East Asian population with an overall allele frequency of 1.9% (389/19954 alleles, including three homozygotes) in the Genome Aggregation Database. The proline at codon 229 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.32). Based on available information, this variant is considered to be mildly pathogenic for Gilbert syndrome with reduced penetrance. References: Ando Y et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 2000 60:6921-6926. PMID: 11156391 Huang CS et al. Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1A1 gene in healthy Taiwanese. Pharmacogenetics. 2000 10:539-544. PMID: 10975608 Kaniwa N et al. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American. Drug Metab Dispos. 2005 33:458-465. PMID: 15572581 Koiwai O et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet. 1995 4:1183-1186. PMID: 8528206 Mackenzie PI et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 1997 7:255-269. PMID: 9295054 Maruo Y et al. 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. Clin Genet. 2003 64:420-423. PMID: 14616765 Sai K et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther. 2004 75:501-515. PMID: 15179405 Sun L et al. Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type II. Medicine (Baltimore). 2017 96:e8620. PMID: 29137095 Teh LK et al. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia. Indian J Med Res. 2012 136:249-259. PMID: 22960892 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 17:1017-1029. PMID: 18004206

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714674.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Apr 20, 2024