Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001962424 | SCV002209094 | uncertain significance | not provided | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the ABCB4 protein (p.Ala286Val). This variant is present in population databases (rs765478923, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of progressive familial intrahepatic cholestasis (PMID: 17726488, 22331132, 23533021). ClinVar contains an entry for this variant (Variation ID: 1434402). 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCB4 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCB4 function (PMID: 24806754, 27256251). 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, |
RCV002469433 | SCV002766039 | uncertain significance | not specified | 2022-11-18 | criteria provided, single submitter | clinical testing | Variant summary: ABCB4 c.857C>T (p.Ala286Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250866 control chromosomes (gnomAD). c.857C>T has been reported in the literature in at least one compound heterozygous individual affected with Progressive Familial Intrahepatic Cholestasis (Degiorgio_2007), and in at least one heterozygous individual affected with low-phospholipid associated cholelithiasis (Wendum_2012, Poupon_2013). These data do not allow any conclusion about variant significance. Two independent experimental studies evaluating the effect of the variant on protein function have shown conflicting evidence: Andress_2014 showed the variant had nearly absent floppase activity and Park_2016 showed no significant differences from wild-type. These studies do not allow for any conclusion about variant significance. One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |