VCV000977762.2 - ClinVar

NC_000012.11:g.21014093_21014094insLINE1

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.

(2)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000012.11:g.21014093_21014094insLINE1

Variation ID: 977762 Accession: VCV000977762.2

Type and length

Insertion, 6,000 bp

Location

Cytogenetic: 12p12.2 12: 21014093-21014094 (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 14, 2020	Oct 7, 2020	Dec 20, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NC_000012.11:g.21014093_21014094insLINE1

Protein change

Other names

Canonical SPDI

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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.

Links

VarSome

Comment on variant

The variant length was curated by NCBI. LINE elements are 4000-7000 bp; a typical LINE is 6000 bp.

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

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 (1)	criteria provided, single submitter	Aug 19, 2014	RCV001255630.1
constitutional indocyanine green excretory defect	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2016	RCV003334396.1

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 (Dec 20, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	constitutional indocyanine green excretory defect (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Liver Center, Tokai University School of Medicine Accession: SCV001426413.1 First in ClinVar: Oct 07, 2020 Last updated: Oct 07, 2020	Publications: PubMed (1) PubMed: 27863442 Comment: All of four Japanese patients with constitutional indocyanine green (ICG) excretory defect, manifesting markedly impaired ICG clearance, had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon … (more) All of four Japanese patients with constitutional indocyanine green (ICG) excretory defect, manifesting markedly impaired ICG clearance, had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon (L1) in intron 5 of SLCO1B3 gene without any pathological variants in SLCO1B1 and SLC10A1 genes. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression. The allele frequency of this variant was 0.054 in a Japanese population. In summary, the L1 insertion in intron 5 of SLCO1B3 gene meets our criteria to be classified as pathogenic based upon segregation studies and functional analysis. (less) Number of individuals with the variant: 4 Age: 44-62 years Sex: mixed Ethnicity/Population group: Japanese Geographic origin: Japan Comment on evidence: Hepatic OATP1B3 expression was absent.
Pathogenic (Aug 19, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing, in vitro	Rotor syndrome (Autosomal recessive inheritance) Affected status: yes, not applicable Allele origin: germline, not applicable	Liver Center, Tokai University School of Medicine Accession: SCV001335282.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (1) PubMed: 25546334 Comment: All of six Japanese patients with clinically diagnosed Rotor syndrome had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon (L1) in intron 5 of SLCO1B3 gene … (more) All of six Japanese patients with clinically diagnosed Rotor syndrome had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon (L1) in intron 5 of SLCO1B3 gene along with a homozygous c.1738C>T (p.R580X) mutation in SLCO1B1 gene. Hepatic mRNA expression analysis revealed that L1 insertion in SLCO1B3 caused a skipping of exon 5 or exons 5-7, resulting in a premature stop codon that generated truncated protein. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression. The allele frequency of this variant was 0.054 in a Japanese population. In summary, the L1 insertion in intron 5 of SLCO1B3 gene meets our criteria to be classified as pathogenic based upon segregation studies and functional analysis. (less) Observation 1: Number of individuals with the variant: 6 Clinical Features: Conjugated hyperbilirubinemia (present) Age: 48-63 years Sex: mixed Ethnicity/Population group: Japanese Geographic origin: Japan Comment on evidence: Simultaneously, all of 6 had a homozygous c.1738C>T (p.R580X) mutation in SLCO1B1 gene. Testing laboratory: Tokai University Testing laboratory interpretation: Pathogenic Observation 2: Sex: mixed Tissue: liver Result: Hepatic mRNA expression analysis revealed that L1 insertion in SLCO1B3 caused a skipping of exon 5 or exons 5-7, resulting in a premature stop codon that generated truncated protein. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression.

Comment:

All of four Japanese patients with constitutional indocyanine green (ICG) excretory defect, manifesting markedly impaired ICG clearance, had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon (L1) in intron 5 of SLCO1B3 gene without any pathological variants in SLCO1B1 and SLC10A1 genes. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression. The allele frequency of this variant was 0.054 in a Japanese population. In summary, the L1 insertion in intron 5 of SLCO1B3 gene meets our criteria to be classified as pathogenic based upon segregation studies and functional analysis.

Comment:

All of six Japanese patients with clinically diagnosed Rotor syndrome had a homozygous insertion of ~6.1-kbp LINE-1 retrotranspozon (L1) in intron 5 of SLCO1B3 gene along with a homozygous c.1738C>T (p.R580X) mutation in SLCO1B1 gene. Hepatic mRNA expression analysis revealed that L1 insertion in SLCO1B3 caused a skipping of exon 5 or exons 5-7, resulting in a premature stop codon that generated truncated protein. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression. The allele frequency of this variant was 0.054 in a Japanese population. In summary, the L1 insertion in intron 5 of SLCO1B3 gene meets our criteria to be classified as pathogenic based upon segregation studies and functional analysis.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Liver Center, Tokai University School of Medicine Accession: SCV001426413.1	Publications PubMed (1)
loss_of_function_variant (SO:0002054)	Method not provided	Hepatic mRNA expression analysis revealed that L1 insertion in SLCO1B3 caused a skipping of exon 5 or exons 5-7, resulting in a premature stop codon that generated truncated protein. Immunohistochemistry confirmed the absence of hepatic OATP1B3 expression.	Liver Center, Tokai University School of Medicine Accession: SCV001335282.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 21, 2023

ClinVar Genomic variation as it relates to human health

NC_000012.11:g.21014093_21014094insLINE1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...