Submissions for variant NM_000443.4(ABCB4):c.1055C>T (p.Pro352Leu)

gnomAD frequency: 0.00018  dbSNP: rs199662246

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001163095	SCV001325100	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 3	2018-06-19	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	RCV001163096	SCV001325101	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2018-06-19	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	RCV001553603	SCV001774519	uncertain significance	not specified	2021-07-22	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.1055C>T (p.Pro352Leu) results in a non-conservative amino acid change in 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 0.00015 in 244890 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00015 vs 0.0022), allowing no conclusion about variant significance. c.1055C>T has been reported in the literature in an individual affected with biliary atresia/chronic liver dysfunction who only carried one detected pathogenic ABCB4 allele (Godro-Gilart_2016). Site-directed mutagenesis experiments showed the variant to have an apical localization similar to that of the wild-type protein but to have reduced expression (about 30% of wild-type), and non-detectable phospatidylcholine efflux activity (Gordo-Gilart_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.
Invitae	RCV001859050	SCV002214021	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 352 of the ABCB4 protein (p.Pro352Leu). This variant is present in population databases (rs199662246, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of ABCB4-related conditions (PMID: 26153658). ClinVar contains an entry for this variant (Variation ID: 910926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26153658). 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.