Submissions for variant NM_000443.4(ABCB4):c.101C>T (p.Thr34Met)

gnomAD frequency: 0.00123  dbSNP: rs142794414

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177067	SCV000228885	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764725	SCV000895860	uncertain significance	Progressive familial intrahepatic cholestasis type 3; Low phospholipid associated cholelithiasis; Cholestasis, intrahepatic, of pregnancy, 3	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000987920	SCV001137413	benign	Progressive familial intrahepatic cholestasis type 1	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000177067	SCV002144136	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 34 of the ABCB4 protein (p.Thr34Met). This variant is present in population databases (rs142794414, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of progressive familial intrahepatic cholestasis or low phospholipid associated cholelithiasis syndrome (PMID: 22331132, 24723470, 28355206). ClinVar contains an entry for this variant (Variation ID: 196273). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ABCB4 function (PMID: 24723470). 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	RCV000177067	SCV003824336	uncertain significance	not provided	2020-12-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537422	SCV004116634	uncertain significance	ABCB4-related disorder	2023-11-29	criteria provided, single submitter	clinical testing	The ABCB4 c.101C>T variant is predicted to result in the amino acid substitution p.Thr34Met. This variant has been reported in the heterozygous state in an individual with low phospholipid-associated cholelithiasis (Wendum et al. 2012. PubMed ID: 22331132, Table 2, Patient 3). In vitro functional studies indicate that this variant does not impact protein stability, expression, and apical plasma membrane localization, but decreases ABCB4-mediated phosphatidylcholine secretion activity and impairs ABCB4 phosphorylation (Gautherot et al. 2014. PubMed ID: 24723470). This variant is reported in 0.48% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV000177067	SCV004224032	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	BS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992213	SCV004810103	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 3	2024-04-04	criteria provided, single submitter	clinical testing