NM_000443.4(ABCB4):c.2800G>A (p.Ala934Thr) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Dec 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000443.4(ABCB4):c.2800G>A (p.Ala934Thr)]

NM_000443.4(ABCB4):c.2800G>A (p.Ala934Thr)

ABCB4:ATP binding cassette subfamily B member 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000443.4(ABCB4):c.2800G>A (p.Ala934Thr)
  • NC_000007.14:g.87412017C>T
  • NG_007118.1:g.73416G>A
  • NG_007118.2:g.73416G>A
  • NM_000443.4:c.2800G>AMANE SELECT
  • NM_018849.3:c.2800G>A
  • NM_018850.2:c.2783+1600G>A
  • NP_000434.1:p.Ala934Thr
  • NP_061337.1:p.Ala934Thr
  • NC_000007.13:g.87041333C>T
  • NM_000443.3:c.2800G>A
  • P21439:p.Ala934Thr
Protein change:
UniProtKB: P21439#VAR_043102; dbSNP: rs61730509
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_018850.2:c.2783+1600G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000443.4:c.2800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_018849.3:c.2800G>A - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000331495EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
(Aug 24, 2015)
germlineclinical testing

Citation Link,

SCV001468271Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Dec 17, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing



Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.

Goldschmidt ML, Mourya R, Connor J, Dexheimer P, Karns R, Miethke A, Sheridan R, Zhang K, Bezerra JA.

Hepatol Res. 2016 Apr;46(4):306-11. doi: 10.1111/hepr.12545. Epub 2015 Jul 14.

PubMed [citation]

Heterozygous ABCB4 mutations in children with cholestatic liver disease.

Gordo-Gilart R, Hierro L, Andueza S, Muñoz-Bartolo G, López C, Díaz C, Jara P, Álvarez L.

Liver Int. 2016 Feb;36(2):258-67. doi: 10.1111/liv.12910. Epub 2015 Aug 3.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000331495.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001468271.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


Variant summary: ABCB4 c.2800G>A (p.Ala934Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 250988 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2800G>A has been reported in the literature in individuals affected with Cholestasis (Rosmorduc_2003, Poupon_2010, Goldschmidt_2016, GordoGilart_2016, Hakim_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abnormal protein localization and decreased activity (Gordo-Gilart_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, benign n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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

Last Updated: Sep 6, 2021

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