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NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe) AND Progressive familial intrahepatic cholestasis

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 2, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003226159.2

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]

Condition(s)

Name:
Progressive familial intrahepatic cholestasis (PFIC)
Synonyms:
Progressive intrahepatic cholestasis; Progressive family intrahepatic cholestasis
Identifiers:
MONDO: MONDO:0015762; MedGen: C0268312; OMIM: PS211600

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003922668Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Mar 2, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma.

de Vries E, Mazzetti M, Takkenberg B, Mostafavi N, Bikker H, Marzioni M, de Veer R, van der Meer A, Doukas M, Verheij J, Beuers U.

Liver Int. 2020 Dec;40(12):3042-3050. doi: 10.1111/liv.14662.

PubMed [citation]
PMID:
32893960

MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.

Rosmorduc O, Hermelin B, Poupon R.

Gastroenterology. 2001 May;120(6):1459-67.

PubMed [citation]
PMID:
11313316

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922668.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: ABCB4 c.959C>T (p.Ser320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251176 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00016 vs 0.0022), allowing no conclusion about variant significance. c.959C>T has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (example: Rosmmorduc_2001 and de Vries_2020). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024