2-233760973-C-T

Variant names:

• chr2-233760973-C-T
• rs35350960
• NM_000463.3:c.686C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_000463.3(UGT1A1):​c.686C>T​(p.Pro229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P229Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.857
• Publications: 107 publications found

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]

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]

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]

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]

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]

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]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.2468 (below the threshold of 3.09). Trascript score misZ: 0.17712 (below the threshold of 3.09). GenCC associations: The gene is linked to Crigler-Najjar syndrome type 1, Crigler-Najjar syndrome type 2, Gilbert syndrome.
• PP5: Variant 2-233760973-C-T is Pathogenic according to our data. Variant chr2-233760973-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1409267.
• BP4: Computational evidence support a benign effect (MetaRNN=0.292236). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A1	NM_000463.3	c.686C>T	p.Pro229Leu	missense_variant	Exon 1 of 5	ENST00000305208.10	NP_000454.1
UGT1A4	NM_007120.3	c.868-6061C>T		intron_variant	Intron 1 of 4	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.868-6061C>T		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6061C>T		intron_variant	Intron 1 of 4	ENST00000482026.6	NP_061966.1
UGT1A6	NM_001072.4	c.862-6061C>T		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-6061C>T		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6061C>T		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6061C>T		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.856-6061C>T		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A1	ENST00000305208.10	c.686C>T	p.Pro229Leu	missense_variant	Exon 1 of 5	1	NM_000463.3	ENSP00000304845.5
UGT1A4	ENST00000373409.8	c.868-6061C>T		intron_variant	Intron 1 of 4	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.868-6061C>T		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.868-6061C>T		intron_variant	Intron 1 of 4	1	NM_019093.4	ENSP00000418532.1
UGT1A6	ENST00000305139.11	c.862-6061C>T		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-6061C>T		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.856-6061C>T		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.856-6061C>T		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-6061C>T		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251388 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.0000426 AC XY: 31 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000356 Hom.: 5

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 1409267). This variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. This variant is present in population databases (rs35350960, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 229 of the UGT1A1 protein (p.Pro229Leu). 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. -

May 21, 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.686C>T; p.Pro229Leu variant (rs35350960) is reported in the literature healthy individuals (Abuli 2016, Kaniwa 2005), but functional analyses of this variant demonstrate poor UGT1A1 protein stability, lowered glucuronidation activity, and the variant is predicted to cause Irinotecan toxicity and hyperbilirubinemia (Kaniwa 2005). This variant is found in the non-Finnish European population with an allele frequency of 0.01% (10/129,092 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.686C>A, p.Pro229Gln, also known as *27), classified as pathogenic-mild, has been reported in individuals with Gilbert syndrome with reduced penetrance (Aono 1995, Gagne 2002, Koiwai 1995, Sun 2017), and may confer an increased risk for drug toxicity when treated with irinotecan (Ando 2000, Teh 2012). Based on available information, the p.Pro229Leu variant is considered to be likely pathogenic-mild for Gilbert syndrome with possible reduced penetrance. Although it is possible that the pharmacogenetic impact of this variant can be similar to that of the p.Pro229Gln variant, additional clinical evidence is warranted to confirm such association. References: -

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 Uncertain:1

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		0.86
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.16
Sift	Benign	0.047	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.94	P;.
Vest4		0.44
MVP		0.62
MPC		0.34
ClinPred		0.31	T
GERP RS		4.9
Varity_R		0.24
gMVP		0.57
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs35350960; hg19: chr2-234669619;