rs72551341

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_000463.3(UGT1A1):c.524T>A(p.Leu175Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

UGT1A1
NM_000463.3 missense

Scores

Clinical Significance

Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.98

Variant links:

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]

UGT1A1 links:

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]

UGT1A4 links:

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]

UGT1A5 links:

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]

UGT1A3 links:

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]

UGT1A6 links:

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]

UGT1A10 links:

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]

UGT1A8 links:

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]

UGT1A7 links:

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]

UGT1A9 links:

UGT1A (HGNC:12529):

UGT1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

PP5

Variant 2-233760811-T-A is Pathogenic according to our data. Variant chr2-233760811-T-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 12285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760811-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A1	NM_000463.3 link	c.524T>A	p.Leu175Gln	missense_variant	Exon 1 of 5	ENST00000305208.10	NP_000454.1	P22309-1Q5DT03
UGT1A4	NM_007120.3 link	c.868-6223T>A		intron_variant	Intron 1 of 4	ENST00000373409.8	NP_009051.1	P22310-1
UGT1A5	NM_019078.2 link	c.868-6223T>A		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1	P35504-1Q5DSZ9
UGT1A3	NM_019093.4 link	c.868-6223T>A		intron_variant	Intron 1 of 4	ENST00000482026.6	NP_061966.1	P35503-1Q5DT01
UGT1A6	NM_001072.4 link	c.862-6223T>A		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2	P19224-1Q5DSZ8
UGT1A10	NM_019075.4 link	c.856-6223T>A		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1	Q9HAW8-1Q5DT02
UGT1A8	NM_019076.5 link	c.856-6223T>A		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3	Q9HAW9-1Q5DSZ6
UGT1A7	NM_019077.3 link	c.856-6223T>A		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2	Q9HAW7-1Q5DSZ7
UGT1A9	NM_021027.3 link	c.856-6223T>A		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1	O60656-1Q5DSZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UGT1A1	ENST00000305208.10 link	c.524T>A	p.Leu175Gln	missense_variant	Exon 1 of 5	1	NM_000463.3	ENSP00000304845.5	P22309-1
UGT1A4	ENST00000373409.8 link	c.868-6223T>A		intron_variant	Intron 1 of 4	1	NM_007120.3	ENSP00000362508.4	P22310-1
UGT1A5	ENST00000373414.4 link	c.868-6223T>A		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3	P35504-1
UGT1A3	ENST00000482026.6 link	c.868-6223T>A		intron_variant	Intron 1 of 4	1	NM_019093.4	ENSP00000418532.1	P35503-1
UGT1A6	ENST00000305139.11 link	c.862-6223T>A		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6	P19224-1
UGT1A10	ENST00000344644.10 link	c.856-6223T>A		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5	Q9HAW8-1
UGT1A9	ENST00000354728.5 link	c.856-6223T>A		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4	O60656-1
UGT1A7	ENST00000373426.4 link	c.856-6223T>A		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3	Q9HAW7-1
UGT1A8	ENST00000373450.5 link	c.856-6223T>A		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4	Q9HAW9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251292

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461070

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic; other

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 175 of the UGT1A1 protein (p.Leu175Gln). This variant is present in population databases (rs72551341, gnomAD 0.009%). This missense change has been observed in individual(s) with UGT1A1-related conditions (PMID: 7989595, 11013440, 11370628, 23290513). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as *12. ClinVar contains an entry for this variant (Variation ID: 12285). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 7989595, 9028453, 19830808). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The UGT1A1 c.524T>A; p.Leu175Gln variant (rs72551341) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with Crigler-Najjar syndrome type II (Kadakol 2001, Seppen 1994). Functional analyses of the variant protein show significantly reduced bilirubin glucuronidation activity (Seppen 1994, Sneitz 2010). This variant is also reported in ClinVar (Variation ID: 12285). This variant is found in the non-Finnish European population with an allele frequency of 0.009% (11/113682 alleles) in the Genome Aggregation Database. The leucine at codon 175 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.494). Based on available information, this variant is considered to be likely pathogenic. References: Kadakol A et al. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet. 2001 Apr;38(4):244-9. PMID: 11370628. Seppen J et al. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest. 1994 Dec;94(6):2385-91. PMID: 7989595. Sneitz N et al. Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat. 2010 Jan;31(1):52-9. PMID: 19830808. -

Mar 08, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Crigler-Najjar syndrome type 1;C0017551:Gilbert syndrome;C0270210:Lucey-Driscoll syndrome;C1866173:Bilirubin, serum level of, quantitative trait locus 1;C2931132:Crigler-Najjar syndrome, type II

Pathogenic:1

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

UGT1A1-related disorder

Pathogenic:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The UGT1A1 c.524T>A variant is predicted to result in the amino acid substitution p.Leu175Gln. This variant has been reported to be causative for Crigler-Najjar type 2 in the homozygous or compound heterozygous state (Seppen et al. 1994. PubMed ID: 7989595; Kadakol et al. 2001. PubMed ID: 11370628). In vitro functional analysis indicated that the p.Leu175Gln change results in a significant loss of enzymatic activity (~4.6% of wild type) (Sneitz et al. 2010. PubMed ID: 19830808). At PreventionGenetics, we have previously detected this variant, along with a protein-truncating variant, in an unrelated patient with suspected Crigler-Najjar syndrome. This variant is reported in 0.0097% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We classify this variant as pathogenic. -

Crigler-Najjar syndrome, type II

Pathogenic:1

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.2

M;M

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.49

Sift

Benign

0.066

T;D

Sift4G

Benign

0.10

T;T

Polyphen

0.95

P;.

Vest4

0.82

MVP

0.72

MPC

0.51

ClinPred

0.74

GERP RS

6.2

Varity_R

0.57

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over