VCV000598092.12 - ClinVar

NM_003742.4(ABCB11):c.2842C>T (p.Arg948Cys)

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/Likely 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_003742.4(ABCB11):c.2842C>T (p.Arg948Cys)

Variation ID: 598092 Accession: VCV000598092.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.1 2: 168935398 (GRCh38) [ NCBI UCSC ] 2: 169791908 (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	Dec 16, 2018	Feb 14, 2024	Oct 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003742.4:c.2842C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003733.2:p.Arg948Cys	missense
NM_003742.2:c.2842C>T
NC_000002.12:g.168935398G>A
NC_000002.11:g.169791908G>A
NG_007374.2:g.100999C>T
LRG_1199:g.100999C>T
LRG_1199t1:c.2842C>T	LRG_1199p1:p.Arg948Cys

... more HGVS ... less HGVS

Protein change

R948C

Other names

Canonical SPDI

NC_000002.12:168935397: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

dbSNP: rs1559183717 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.
ABCB11		-	-	GRCh38 GRCh38 GRCh37	1502	1605
LOC126806400	-	-	-	GRCh38 GRCh38	-	88

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 27, 2023	RCV000734399.11
Benign recurrent intrahepatic cholestasis type 2 Progressive familial intrahepatic cholestasis type 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 26, 2021	RCV002477730.1
Progressive familial intrahepatic cholestasis	Pathogenic (1)	criteria provided, single submitter	Feb 28, 2023	RCV003155301.1
Benign recurrent intrahepatic cholestasis type 2	Pathogenic (1)	criteria provided, single submitter	Oct 7, 2023	RCV003472270.1

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 (Jul 19, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000862538.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Publications: PubMed (4) PubMed: 20683201‚ 26678486‚ 18395098‚ 19101985 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB11 Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (Aug 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive familial intrahepatic cholestasis type 2 Benign recurrent intrahepatic cholestasis type 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002789588.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001589179.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 18395098‚ 20683201‚ 26678486‚ 19101985 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 948 of the ABCB11 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 948 of the ABCB11 protein (p.Arg948Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ABCB11-related disease (PMID: 18395098, 20683201, 26678486). ClinVar contains an entry for this variant (Variation ID: 598092). 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 expected to disrupt ABCB11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 19101985). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Progressive familial intrahepatic cholestasis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003844315.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (3) PubMed: 19101985‚ 18395098‚ 26678486 Comment: Variant summary: ABCB11 c.2842C>T (p.Arg948Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein … (more) Variant summary: ABCB11 c.2842C>T (p.Arg948Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248970 control chromosomes. c.2842C>T has been reported in the literature in individuals affected with Intrahepatic Cholestasis (Strautnieks_2008, Giovannoni_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant effect results in immature protein (Byrne_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Oct 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Benign recurrent intrahepatic cholestasis type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202559.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 948 of the ABCB11 protein (p.Arg948Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ABCB11-related disease (PMID: 18395098, 20683201, 26678486). ClinVar contains an entry for this variant (Variation ID: 598092). 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 expected to disrupt ABCB11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 19101985). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: ABCB11 c.2842C>T (p.Arg948Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248970 control chromosomes. c.2842C>T has been reported in the literature in individuals affected with Intrahepatic Cholestasis (Strautnieks_2008, Giovannoni_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant effect results in immature protein (Byrne_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified 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
Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center.	Giovannoni I	PloS one	2015	PMID: 26678486
Analysis of gene mutations in children with cholestasis of undefined etiology.	Matte U	Journal of pediatric gastroenterology and nutrition	2010	PMID: 20683201
Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.	Byrne JA	Hepatology (Baltimore, Md.)	2009	PMID: 19101985
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.	Strautnieks SS	Gastroenterology	2008	PMID: 18395098
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB11	-	-	-	-

Text-mined citations for rs1559183717 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003742.4(ABCB11):c.2842C>T (p.Arg948Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1559183717 ...