VCV000012288.18 - ClinVar

NM_001072.4(UGT1A6):c.862-10021T>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001072.4(UGT1A6):c.862-10021T>G

Variation ID: 12288 Accession: VCV000012288.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.1 2: 233757013 (GRCh38) [ NCBI UCSC ] 2: 234665659 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 30, 2017	Mar 4, 2023	Aug 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001072.4:c.862-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_007120.3:c.868-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019075.4:c.856-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019076.5:c.856-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019077.3:c.856-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019078.2:c.868-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_019093.4:c.868-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_021027.3:c.856-10021T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_205862.3:c.61-10021T>G		intron variant
NC_000002.12:g.233757013T>G
NC_000002.11:g.234665659T>G
NG_002601.2:g.172270T>G
NG_033238.1:g.1741T>G
LRG_733:g.1741T>G
LRG_733t1:c.-3275T>G

... more HGVS ... less HGVS

Protein change

Other names

-3263T-G, PROMOTER

Canonical SPDI

NC_000002.12:233757012:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.41194 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.56024

The Genome Aggregation Database (gnomAD) 0.54847

Trans-Omics for Precision Medicine (TOPMed) 0.56372

Trans-Omics for Precision Medicine (TOPMed) 0.55247

1000 Genomes Project 0.58806

Links

ClinGen: CA122117 OMIM: 191740.0024 dbSNP: rs4124874 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PMID 11906189 Fig. 1 to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
UGT1A	-	-	-	GRCh38	-	587
UGT1A1		-	-	GRCh38 GRCh37	2	371
UGT1A10		-	-	GRCh38 GRCh37	-	589
UGT1A3		-	-	GRCh38 GRCh37	-	395
UGT1A4		-	-	GRCh38 GRCh37	-	421
UGT1A5		-	-	GRCh38 GRCh37	-	439
UGT1A6		-	-	GRCh38 GRCh37	-	482
UGT1A7		-	-	GRCh38 GRCh37	-	534
UGT1A8		-	-	GRCh38 GRCh37	-	617
UGT1A9		-	-	GRCh38 GRCh37	-	569

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Gilbert syndrome, susceptibility to	risk factor (1)	no assertion criteria provided	Nov 1, 2004	RCV000013082.12
Gilbert syndrome	Likely pathogenic (2)	criteria provided, single submitter	-	RCV000999557.11
not provided	Benign (1)	criteria provided, single submitter	Aug 19, 2022	RCV001810854.17

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gilbert syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426571.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Benign (Aug 19, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605521.7 First in ClinVar: Sep 30, 2017 Last updated: Mar 04, 2023
risk factor (Nov 01, 2004)	no assertion criteria provided Method: literature only	GILBERT SYNDROME, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033328.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2017	Publications: PubMed (2) PubMed: 11906189‚ 15378351 Comment on evidence: Sugatani et al. (2002) identified a SNP, -3263T-G, in the UGT1A1 promoter, also known as the phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3). Functional studies … (more) Sugatani et al. (2002) identified a SNP, -3263T-G, in the UGT1A1 promoter, also known as the phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3). Functional studies showed that the polymorphism decreased transcriptional activity to approximately 62% of wildtype. Sugatani et al. (2002) identified the -3263T-G polymorphism in 21 of 25 patients with Gilbert syndrome (143500); 8 patients were homozygous and 13 were heterozygous. Five of the homozygotes were also homozygous for the (TA)7 mutation (191740.0011). Twelve of the polymorphism heterozygotes and 1 of the homozygotes were also heterozygous for the G71R mutation (191740.0016). Two of the 21 patients were compound heterozygotes for the -3263T-G polymorphism, the (TA)7 mutation, and the G71R mutation. Of the 4 individuals with Gilbert syndrome without the -3263T-G polymorphism, 3 had the G71R mutation (1 heterozygote and 2 homozygotes) and 1 had no detectable changes in the UGT1A1 gene. In the control group, 8 of 27 individuals had the -3263T-G polymorphism. The frequency of alleles carrying the polymorphism was significantly higher in the hyperbilirubinemic group than in the control group (0.58 vs 0.17, respectively). Plasma total bilirubin levels in the double heterozygotes were significantly higher than those with a single mutation or polymorphism, indicating that those individuals who are heterozygous for the -3263T-G polymorphism and for the G71R mutation are predisposed for hyperbilirubinemia in Gilbert syndrome. Maruo et al. (2004), who referred to this polymorphism as T-3279G, studied 11 Caucasians and 12 Japanese patients with Gilbert syndrome and found that all 23 patients were homozygous for both A(TA)7TAA and -3263T-G, indicating that the 2 polymorphisms are linked. They suggested that the decrease of transcription caused by both mutations may be essential to the development of Gilbert syndrome. (less)
Pathogenic (May 01, 2019)	no assertion criteria provided Method: case-control	Gilbert syndrome Affected status: yes Allele origin: inherited	Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University Accession: SCV001156250.1 First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020	Number of individuals with the variant: 101 Age: 25-55 years Sex: mixed Ethnicity/Population group: Chinese

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome.	Maruo Y	Human genetics	2004	PMID: 15378351
Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia.	Sugatani J	Biochemical and biophysical research communications	2002	PMID: 11906189

Text-mined citations for rs4124874 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 11, 2023

ClinVar Genomic variation as it relates to human health

NM_001072.4(UGT1A6):c.862-10021T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs4124874 ...