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

gnomAD frequency: 0.00389  dbSNP: rs61730509

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000322710	SCV000331495	benign	not specified	2015-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000413855	SCV000491318	likely pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; in vitro functional studies showed the A934T allele leads 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); 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: 26153658, 26900700, 23533021, 27825922, 22527017, 31538484, 17562004, 16622704, 32893960, 30954630, 33742171, 12891548, 20537830, 34016879, 35894240, 35654975, 31000363, 35922258)
Mendelics	RCV000987905	SCV001137398	uncertain significance	Progressive familial intrahepatic cholestasis type 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV001164953	SCV001327116	uncertain significance	Progressive familial intrahepatic cholestasis type 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	2023-12-07	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), strongly 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, Gordo-Gilart_LiverInt_2016, Hakim_2019, Hertel_2021, Nayagam_2022, Halleb_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. At least two publications reported experimental evidence evaluating an impact on protein function and showed that this variant results in abnormal protein localization and decreased activity (Gordo-Gilart_ LiverInt_2016, Gordo-Gilart_PLoSOne_2016). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=1), benign (n=1) and uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252078	SCV002522888	uncertain significance	See cases	2023-10-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3, BS2, PM3
Mayo Clinic Laboratories, Mayo Clinic	RCV000413855	SCV002542281	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	BS1, PP3
Invitae	RCV000413855	SCV003245501	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 934 of the ABCB4 protein (p.Ala934Thr). This variant is present in population databases (rs61730509, gnomAD 1.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy or low phospholipid associated cholelithiasis syndrome although a second variant is not observed in some of the individuals (PMID: 12891548, 18482588, 23533021, 26153658, 31000363). ClinVar contains an entry for this variant (Variation ID: 281139). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCB4 function (PMID: 26153658, 26900700). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000413855	SCV003824341	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401229	SCV004105874	uncertain significance	ABCB4-related condition	2023-11-16	criteria provided, single submitter	clinical testing	The ABCB4 c.2800G>A variant is predicted to result in the amino acid substitution p.Ala934Thr. This variant has been reported in the homozygous and compound heterozygous states in patients with cholelithiasis, cholestasis and chronic liver disease (Rosmorduc et al. 2003. PubMed ID: 12891548; Hertel et al. 2021. PubMed ID: 34016879; Hakim et al. 2019. PubMed ID: 31000363; Table S1, Nayagam et al. 2022. PubMed ID: 35894240). Further, an in vitro functional study supports its pathogenicity (Gordo-Gilart et al. 2016. PubMed ID: 26153658). However, this variant is reported in 1.4% of alleles in individuals of African descent in gnomAD, including a single homozygous individual. This population frequency is significantly higher than other known pathogenic variants in this gene. It has conflicting interpretations of pathogenicity in the ClinVar database ranging from benign to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/281139/). Variable expressivity, incomplete penetrance, and/or other genetic modifiers could be playing a role in this variant's contribution to disease risk (Colombo et al. 2011. PubMed ID: 21119540). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV001164953	SCV004024100	likely pathogenic	Progressive familial intrahepatic cholestasis type 3		no assertion criteria provided	research