NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Oct 15, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000498517.31

Allele description [Variation Report for NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)]

NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)

Gene:

ABCB4:ATP binding cassette subfamily B member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.12

Genomic location:

Preferred name:

NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)

HGVS:

NC_000007.14:g.87447080G>A
NG_007118.2:g.38353C>T
NM_000443.4:c.959C>TMANE SELECT
NM_018849.3:c.959C>T
NM_018850.3:c.959C>T
NP_000434.1:p.Ser320Phe
NP_061337.1:p.Ser320Phe
NP_061338.1:p.Ser320Phe
NC_000007.13:g.87076396G>A
NM_000443.3:c.959C>T
NM_018849.2:c.959C>T
P21439:p.Ser320Phe

Protein change:

S320F; SER320PHE

Links:

UniProtKB: P21439#VAR_023502; OMIM: 171060.0005; dbSNP: rs72552778

NCBI 1000 Genomes Browser:

rs72552778

Molecular consequence:

NM_000443.4:c.959C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018849.3:c.959C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018850.3:c.959C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589676	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 15, 2024)	germline	clinical testing	Citation Link,
SCV000706335	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Aug 24, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11313316, 12891548, 16890614, 17726488, 19840255, 21119540, 24381502, 24806754 Citation Link,
SCV001931835	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001962061	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2021)	germline	clinical testing	Citation Link,
SCV001968202	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV003457569	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11313316, 32893960, 24806754, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	9	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ABCB4 gene mutation-associated cholelithiasis in adults.

Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R.

Gastroenterology. 2003 Aug;125(2):452-9.

PubMed [citation]

PMID:: 12891548

Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy.

Keitel V, Vogt C, Häussinger D, Kubitz R.

Gastroenterology. 2006 Aug;131(2):624-9.

PubMed [citation]

PMID:: 16890614

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000589676.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

One in vitro study showed decreased transport activity, while another showed reduced protein expression but normal protein function (PMID: 26153658, 24381502); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19490418, 17562004, 26699824, 23533021, 24381502, 22331132, 11313316, 19840255, 17786139, 19584064, 15077010, 16890614, 17726488, 21119540, 26324191, 28776642, 29761167, 24806754, 28733223, 30487145, 31538484, 32793533, 32581362, 35288833, 37822304, 34376370, 33258288, 36330364, 33390354, 32893960, 32650689, 26153658)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000706335.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		9	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931835.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001962061.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968202.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003457569.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the ABCB4 protein (p.Ser320Phe). This variant is present in population databases (rs72552778, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of autosomal recessive progressive familial intrahepatic cholestasis type 3 (PMID: 11313316, 32893960). ClinVar contains an entry for this variant (Variation ID: 13690). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 24806754). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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