rs4148323

Positions:

• chr2-233760498-G-A
• chr2-233760498-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BA1

The NM_000463.3(UGT1A1):​c.211G>A​(p.Gly71Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00922 in 1,614,236 control chromosomes in the GnomAD database, including 811 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (90 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (721 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; drug response criteria provided, conflicting classifications P:10 U:2 B:4 O:4
• Conservation: PhyloP100: 3.90

Genes affected

UGT1A1 (HGNC:12530): (UDP glucuronosyltransferase family 1 member A1) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The preferred substrate of this enzyme is bilirubin, although it also has moderate activity with simple phenols, flavones, and C18 steroids. Mutations in this gene result in Crigler-Najjar syndromes types I and II and in Gilbert syndrome. [provided by RefSeq, Jul 2008]

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [provided by RefSeq, Jul 2008]

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. [provided by RefSeq, Jul 2008]

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenols. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a mutagenesis_site Decreased SN-38 glucuronosyltransferase activity. (size 0) in uniprot entity UD11_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016674995).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A1	NM_000463.3	c.211G>A	p.Gly71Arg	missense_variant	1/5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.862-6536G>A		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.868-6536G>A		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-6536G>A		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6536G>A		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6536G>A		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.868-6536G>A		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6536G>A		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A9	NM_021027.3	c.856-6536G>A		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A1	ENST00000305208.10	c.211G>A	p.Gly71Arg	missense_variant	1/5	1	NM_000463.3	ENSP00000304845	P1
UGT1A6	ENST00000305139.11	c.862-6536G>A		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-6536G>A		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-6536G>A		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.868-6536G>A		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.868-6536G>A		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-6536G>A		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-6536G>A		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A3	ENST00000482026.6	c.868-6536G>A		intron_variant		1	NM_019093.4	ENSP00000418532	P1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1720 AN: 152230 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.0223 AC: 5619 AN: 251430 Hom.: 276 AF XY: 0.0215 AC XY: 2923 AN XY: 135890

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00901 AC: 13165 AN: 1461888 Hom.: 721 Cov.: 34 AF XY: 0.00931 AC XY: 6769 AN XY: 727246

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0428

Gnomad4 NFE exome AF: 0.000782

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0113 AC: 1721 AN: 152348 Hom.: 90 Cov.: 33 AF XY: 0.0151 AC XY: 1127 AN XY: 74498

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.0472

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00667 Hom.: 150

Bravo AF: 0.0100

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0207 AC: 2507

Asia WGS AF: 0.0630 AC: 220 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity; drug response

Submissions summary: Pathogenic:10 Uncertain:2 Benign:4 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2021	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, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2023	- -

Gilbert syndrome Pathogenic:2 Benign:2 Other:2

other, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 25, 2016	- reduced function allele
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	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. -
Affects, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, no assertion criteria provided	case-control	Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University	May 01, 2019	- -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2014	- -

Lucey-Driscoll syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

Crigler-Najjar syndrome, type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Irinotecan response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Apr 04, 2018

UGT1A1*6 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. Poor metabolizer

Bilirubin, serum level of, quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.60	P;P;P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.14
Sift	Benign	0.040	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.98	D;.
Vest4		0.067
MutPred		0.57		Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);
MPC		0.34
ClinPred		0.032	T
GERP RS		5.1
Varity_R		0.17
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4148323; hg19: chr2-234669144; COSMIC: COSV59383881; COSMIC: COSV59383881;