ClinVar Miner

Submissions for variant NM_000443.4(ABCB4):c.2800G>A (p.Ala934Thr) (rs61730509)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000322710 SCV000331495 benign not specified 2015-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000413855 SCV000491318 likely pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing The A934T variant has been reported previously as homozygous in one individual with low phospholipid-associated cholelithiasis (LPAC) syndrome; heterozygous parents were asymptomatic (Rosmorduc et al., 2003). The A934T variant was also reported as heterozygous in an individual with cholestatic liver disease; a second variant in the ABCB4 gene was not identified (Gordo-Gilart et al., 2016). In vitro functional studies showed the A934T allele lead to reduced MDR3 protein levels (65%) and MDR3 activity (50%), which resulted in trapping of the ABCB4 protein in the endoplasmic reticulum (Gordo-Gilart et al., 2016). The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium reports A934T was observed in 1.2-2.8% of alleles from individuals of African background. The A934T variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Mendelics RCV000987905 SCV001137398 uncertain significance Cholestasis, progressive familial intrahepatic 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001164952 SCV001327115 uncertain significance Cholestasis, intrahepatic, of pregnancy 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001164953 SCV001327116 uncertain significance Progressive familial intrahepatic cholestasis 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000322710 SCV001468271 uncertain significance not specified 2020-12-17 criteria provided, single submitter clinical testing 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.

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