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

dbSNP: rs35350960

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147905	SCV000195396	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000299521	SCV000344304	other	not provided	2018-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000299521	SCV001111446	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000299521	SCV001156826	pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000147905	SCV001653054	uncertain significance	not specified	2020-06-19	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000299521	SCV001714674	pathogenic	not provided	2020-07-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532328	SCV004120217	uncertain significance	UGT1A1-related disorder	2024-02-08	criteria provided, single submitter	clinical testing	The UGT1A1 c.686C>A variant is predicted to result in the amino acid substitution p.Pro229Gln. The minor allele frequency of this variant is over 1% in the East Asian sub-population, including 3 homozygotes, indicating this variant may be too common to be a primary cause of a Mendelian disease. However, an in vitro study indicated this variant caused a reduction in the activity of bilirubin UDP-glucuronosyltransferase (UGT) (Koiwai et al. 1995. PubMed ID: 8528206). The contribution of this variant to disease remains under debate (Kaniwa et al. 2005. PubMed ID: 15572581; Zhang et al. 2007. PubMed ID: 17060921; Wisnumurti et al. 2018. PubMed ID: 29607327), and classifications for this variant from outside laboratories range from benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12274/). Therefore, we classify c.686C>A (p.Pro229Gln) as a variant of uncertain significance.
OMIM	RCV000013062	SCV000033308	affects	Gilbert syndrome	2007-12-01	no assertion criteria provided	literature only
OMIM	RCV000013063	SCV000033309	pathogenic	Crigler-Najjar syndrome, type II	2007-12-01	no assertion criteria provided	literature only
Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University	RCV000013062	SCV001156254	pathogenic	Gilbert syndrome	2019-05-01	no assertion criteria provided	case-control