Submissions for variant NM_000443.4(ABCB4):c.2324C>T (p.Thr775Met)

gnomAD frequency: 0.00039  dbSNP: rs148052192

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001161448	SCV001323330	likely benign	Cholestasis, intrahepatic, of pregnancy, 3	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics	RCV001331236	SCV001523231	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2020-03-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV002032491	SCV002201625	uncertain significance	not provided	2022-07-19	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 775 of the ABCB4 protein (p.Thr775Met). This variant is present in population databases (rs148052192, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ABCB4-related conditions (PMID: 17726488, 22331132). ClinVar contains an entry for this variant (Variation ID: 909965). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ABCB4 function (PMID: 26474921). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265956	SCV002548019	uncertain significance	not specified	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.2324C>T (p.Thr775Met) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 251208 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00051 vs 0.0022), allowing no conclusion about variant significance. c.2324C>T has been reported in the literature as a paternally inherited complex allele in cis with p.F357L along with a different maternally inherited variant in an individual with Progressive familial intrahepatic cholestasis type 3 (PFIC3), it has also been reported in isolation as a presumed compound heterozygous genotype in an individual with a form of cholelithiasis referred to as LPAC syndrome (example, Degiorgio_2007, Poupon_2010). These two reports have been cited by others (example, Wendum_2012, Delaunay_2016) and one study reports this variant as a VUS with a likely pathogenic variant in the TJP2 gene in a male with cholestasis (example, Vitale_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Delaunay_2016). The most pronounced variant effect results in >75% of normal Phosphatidylcholine secretion activity for this variant in isolation which decreased further to approximately 20% of normal for the complex allele with p.Phe357Leu. The variant was categorized as Class III with little or no effect on maturation while causing defective activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV002032491	SCV002821818	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	ABCB4: PM3, PM2:Supporting, PP4, PS3:Supporting