rs35003977

Variant names:

• chr2-233760961-T-G
• rs35003977
• NM_000463.3:c.674T>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_000463.3(UGT1A1):​c.674T>G​(p.Val225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,614,200 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:8 U:9 O:1
• Conservation: PhyloP100: 0.407

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP5: Variant 2-233760961-T-G is Pathogenic according to our data. Variant chr2-233760961-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 160239.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, other=1, Uncertain_significance=7, Pathogenic=1}. Variant chr2-233760961-T-G is described in Lovd as [Pathogenic]. Variant chr2-233760961-T-G is described in Lovd as [Likely_pathogenic]. Variant chr2-233760961-T-G is described in Lovd as [Pathogenic]. Variant chr2-233760961-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.008645862). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A1	NM_000463.3	c.674T>G	p.Val225Gly	missense_variant	Exon 1 of 5	ENST00000305208.10	NP_000454.1
UGT1A4	NM_007120.3	c.868-6073T>G		intron_variant	Intron 1 of 4	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.868-6073T>G		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6073T>G		intron_variant	Intron 1 of 4	ENST00000482026.6	NP_061966.1
UGT1A6	NM_001072.4	c.862-6073T>G		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-6073T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6073T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6073T>G		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.856-6073T>G		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.674T>G	p.Val225Gly	missense_variant	Exon 1 of 5	1	NM_000463.3	ENSP00000304845.5
UGT1A4	ENST00000373409.8	c.868-6073T>G		intron_variant	Intron 1 of 4	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.868-6073T>G		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.868-6073T>G		intron_variant	Intron 1 of 4	1	NM_019093.4	ENSP00000418532.1
UGT1A6	ENST00000305139.11	c.862-6073T>G		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-6073T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.856-6073T>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.856-6073T>G		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-6073T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000589 AC: 148 AN: 251456 Hom.: 1 AF XY: 0.000728 AC XY: 99 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000497 AC: 727 AN: 1461894 Hom.: 4 Cov.: 34 AF XY: 0.000568 AC XY: 413 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:8 Uncertain:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:2 Other:1

May 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The UGT1A1 c.674T>G; p.Val225Gly variant (rs35003977), is reported in the literature in individuals with Crigler-Najjar syndrome or Gilbert syndrome with other UGT1A1 variants in cis and/or trans (Iolascon 2000, Maruo 2015, Perretti 2007, Rodrigues 2012). Functional studies show that the variant protein enzymatic activity is reduced compared to that of the wildtype UGT1A1 protein (Maruo 2015). The p.Val225Gly variant is also reported in ClinVar (Variation ID: 160239). It is observed in the general population with an overall allele frequency of 0.05% (153/282862 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.291). Based on available information, the clinical significance of this variant is uncertain at this time. References: Iolascon A et al. Crigler-Najjar syndrome type II resulting from three different mutations in the bilirubin uridine 5'-diphosphate-glucuronosyltransferase (UGT1A1) gene. J Med Genet. 2000 Sep;37(9):712-3. PMID: 11182932. Maruo Y et al. Two Different UGT1A1 Mutations causing Crigler-Najjar Syndrome types I and II in an Iranian Family. J Gastrointestin Liver Dis. 2015 Dec;24(4):523-6. PMID: 26697581. Perretti A et al. Clinical utility of electrophysiological evaluation in Crigler-Najjar syndrome. Neuropediatrics. 2007 Aug;38(4):173-8. PMID: 18058623. Rodrigues C et al. Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects. Blood Cells Mol Dis. 2012 Mar 15;48(3):166-72. PMID: 22325916. -

Feb 09, 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).

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 225 of the UGT1A1 protein (p.Val225Gly). This variant is present in population databases (rs35003977, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyperbilirubinemia (PMID: 11182932, 15712364, 26697581). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 160239). 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: 26697581). For these reasons, this variant has been classified as Pathogenic. -

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PS3 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gilbert syndrome Uncertain:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Crigler-Najjar syndrome Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The UGT1A1 c.674T>G (p.Val225Gly) variant is reported in a total of six individuals with Crigler-Najjar syndrome, including five compound heterozygotes and one heterozygote in whom a second variant was not identified (Iolascon et al. 2000; Servedio et al. 2005; Maruo et al. 2015). The variant was also found in one unaffected heterozygous parent of an affected individual. The p.Val225Gly variant was absent from 150 total controls but is reported at a frequency of 0.00212 in the South Asian population of the Exome Aggregation Consortium. Enzyme activity of the p.Val225Gly variant protein was found to be 61% as compared to wild type (Maruo et al. 2015). Based on the evidence, the p.Val225Gly variant is classified as likely pathogenic for Crigler-Najjar syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases Pathogenic:1

Aug 23, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674T>G (p.V225G) alteration is located in exon 1 (coding exon 1) of the UGT1A1 gene. This alteration results from a T to G substitution at nucleotide position 674, causing the valine (V) at amino acid position 225 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.054% (153/282862) total alleles studied. The highest observed frequency was 0.265% (81/30616) of South Asian alleles. This variant has been detected in the compound heterozygous state with other UGT1A1 variants in multiple individuals diagnosed with Crigler-Najjar syndrome (Iolascon, 2000; Servedio, 2005; Maruo, 2015). This amino acid position is not well conserved in available vertebrate species. Functional studies showed residual enzyme activity of the variant protein was 61% of wild type (Maruo, 2015). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Crigler-Najjar syndrome, type II Pathogenic:1

Aug 03, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.054%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000160239 /PMID: 11182932). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not specified Uncertain:1

Jan 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: UGT1A1 c.674T>G (p.Val225Gly), also reported as V224G, results in a non-conservative amino acid change located in the UDP-glucuronosyl/UDP-glucosyltransferase domain (IPR002213) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 1614200 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately equal to the universal maximal expected allele frequency (MPAF) for a recessive pathogenic variant in any gene, however multiple high frequency variants in the UGT1A1 gene have been classified as pathogenic and our laboratory has not yet established an MPAF specific for UGT1A1. c.674T>G has been reported in the literature in the presumed or confirmed compound heterozygous or complex/multiply heterozygous state in multiple individuals affected with UGT1A1-Related Disorders (e.g., Huang_2006, Iolascon_2000, Maruo_2015, Minucci_2012, Servedio_2005, Kadakol_2000, Rodrigues_2012, Perretti_2007). These data indicate that the variant is possibly associated with disease, however none of the individuals had the severe Crigler-Najjar type I presentation and all except one (Rodrigues_2012) individual had additional variants which could explain the phenotype (e.g. promoter TA(7) expansion, a common pathogenic variant). At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Maruo_2015). The most pronounced variant effect resulted in approximately 60% normal activity for bilirubin glucuronidation compared to the wild type enzyme, however the wild type control had at least 1 replicate with results overlapping the variant enzyme activity result(s), suggesting that the difference may not be statistically significant. The following publications have been ascertained in the context of this evaluation (PMID: 17098698, 11182932, 26697581, 22633750, 15712364, 11013440, 18058623, 22325916). ClinVar contains an entry for this variant (Variation ID: 160239). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lucey-Driscoll syndrome Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

UGT1A1-related disorder Uncertain:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The UGT1A1 c.674T>G variant is predicted to result in the amino acid substitution p.Val225Gly. This variant has been reported in patients affected by Crigler-Najjar Syndrome or Gilbert Syndrome (Iolascon et al. 2000. PubMed ID: 11182932, reported as V224G; Rodrigues et al. 2012. PubMed ID: 22325916; Maruo et al. 2015. PubMed ID: 26697581). In vitro enzymatic activity analysis indicated that the relative glucuronidation activity of the variant protein towards bilirubin was reduced to ~60% of that of wild type (Maruo et al. 2015. PubMed ID: 26697581). Taken together, although we suspect that c.674T>G (p.Val225Gly) could be pathogenic, the clinical significance of this variant is classified as uncertain at this time. -

Hyperbilirubinemia Uncertain:1

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Crigler-Najjar syndrome type 1 Uncertain:1

Mar 28, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	6.1
DANN	Benign	0.64
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.7	M;M
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.29
Sift	Benign	0.32	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.026	B;.
Vest4		0.18
MVP		0.26
MPC		0.15
ClinPred		0.045	T
GERP RS		0.79
Varity_R		0.28
gMVP		0.59

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: rs35003977; hg19: chr2-234669607;