VCV000030488.9 - ClinVar

NM_019844.4(SLCO1B3):c.1747+1G>A

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_019844.4(SLCO1B3):c.1747+1G>A

Variation ID: 30488 Accession: VCV000030488.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.2 12: 20898501 (GRCh38) [ NCBI UCSC ] 12: 21051435 (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	Apr 4, 2013	Oct 8, 2024	Dec 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_019844.4:c.1747+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001349920.2:c.1663+1G>A		splice donor
NM_001371097.1:c.1747+1G>A		splice donor
NC_000012.12:g.20898501G>A
NC_000012.11:g.21051435G>A
NG_032071.2:g.92798G>A

... more HGVS ... less HGVS

Protein change

Other names

SLCO1B3, IVS13, G-A, +1

Canonical SPDI

NC_000012.12:20898500:G:A

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

OMIM: 605495.0002 dbSNP: rs373707046 VarSome

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.
SLCO1B3		-	-	GRCh38 GRCh37	10	314
SLCO1B3-SLCO1B7	-	-	-	GRCh38	-	321

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.
Rotor syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 9, 2022	RCV000023445.9
SLCO1B3-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 11, 2024	RCV003415733.6

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.
Pathogenic (Mar 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rotor syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836352.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rotor syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV004013816.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 22232210 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is predicted to alter splicing … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with SLCO1B1 related disorder (ClinVar ID: VCV000030488 / PMID: 22232210). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Jaundice (present) , Conjugated hyperbilirubinemia (present) , Elevated circulating alanine aminotransferase concentration (present)
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Rotor syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002819408.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Publications: PubMed (3) PubMed: 30366773‚ 32082363‚ 22232210 Comment: Variant summary: SLCO1B3 c.1747+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: SLCO1B3 c.1747+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.2e-06 in 245200 control chromosomes. c.1747+1G>A has been reported in the literature in individuals affected with Rotor Syndrome who carry a pathogenic variant in SLCO1B1 (Zhou_2019, van de Steeg_2012 and Chen_2019). It has been shown that digenic pathogenic variants in SLCO1B1 and SLCO1B3 cause Rotor syndrome (GeneReviews, NCBI Bookshelf). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 01, 2012)	no assertion criteria provided Method: literature only	HYPERBILIRUBINEMIA, ROTOR TYPE, DIGENIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044736.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 22232210 Comment on evidence: In a Filipino patient with Rotor-type hyperbilirubinemia (237450), van de Steeg et al. (2012) identified 2 different homozygous mutations affecting 2 different genes. One was … (more) In a Filipino patient with Rotor-type hyperbilirubinemia (237450), van de Steeg et al. (2012) identified 2 different homozygous mutations affecting 2 different genes. One was a homozygous G-to-A transition in intron 13 of the SLCO1B3 gene (1747+1G-A), predicted to result either in an aberrant transcript or in a truncated protein, and the other was a homozygous truncating mutation in the SLCO1B1 gene (R253X; 604843.0003). (less)
Pathogenic (Sep 11, 2024)	no assertion criteria provided Method: clinical testing	SLCO1B3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113155.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The SLCO1B3 c.1747+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, referred to as the "R3" haplotype … (more) The SLCO1B3 c.1747+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, referred to as the "R3" haplotype when in cis to SLCO1B1 c.757C>T (p.Arg253*), has been reported in the compound heterozygous and homozygous states in multiple individuals with Rotor syndrome (van de Steeg et al. 2012. PubMed ID: 22232210; Zhou et al. 2020. PubMed ID: 32082363; Cheng et al. 2023. PubMed ID: 36964102). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as pathogenic. (less)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with SLCO1B1 related disorder (ClinVar ID: VCV000030488 / PMID: 22232210). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: SLCO1B3 c.1747+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.2e-06 in 245200 control chromosomes. c.1747+1G>A has been reported in the literature in individuals affected with Rotor Syndrome who carry a pathogenic variant in SLCO1B1 (Zhou_2019, van de Steeg_2012 and Chen_2019). It has been shown that digenic pathogenic variants in SLCO1B1 and SLCO1B3 cause Rotor syndrome (GeneReviews, NCBI Bookshelf). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The SLCO1B3 c.1747+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, referred to as the "R3" haplotype when in cis to SLCO1B1 c.757C>T (p.Arg253*), has been reported in the compound heterozygous and homozygous states in multiple individuals with Rotor syndrome (van de Steeg et al. 2012. PubMed ID: 22232210; Zhou et al. 2020. PubMed ID: 32082363; Cheng et al. 2023. PubMed ID: 36964102). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Insertion of LINE-1 Retrotransposon Inducing Exon Inversion Causes a Rotor Syndrome Phenotype.	Zhou D	Frontiers in genetics	2020	PMID: 32082363
Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges.	Chen HL	The Journal of pediatrics	2019	PMID: 30366773
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.	van de Steeg E	The Journal of clinical investigation	2012	PMID: 22232210

Text-mined citations for rs373707046 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_019844.4(SLCO1B3):c.1747+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs373707046 ...