Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001214261 | SCV001385936 | likely pathogenic | not provided | 2024-04-18 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1210 of the ABCB11 protein (p.Thr1210Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ABCB11-related conditions (PMID: 18395098, 28733223). ClinVar contains an entry for this variant (Variation ID: 943967). 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 ABCB11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 19101985, 22609309, 25716872). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV003469360 | SCV004196770 | pathogenic | Benign recurrent intrahepatic cholestasis type 2 | 2024-01-25 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV005021515 | SCV005653413 | likely pathogenic | Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2 | 2024-03-10 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV001828705 | SCV005907426 | likely pathogenic | Progressive familial intrahepatic cholestasis type 2 | 2025-01-23 | criteria provided, single submitter | curation | The p.Thr1210Pro variant in ABCB11 has been identified in 3 individuals with BSEP deficiency (PMID: 18395098, 22609309, 28733223), and has been identified in 0.0002% (3/1178890) of European (non-Finish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1691232631). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 943967) and has been interpreted as pathogenic by Baylor Genetics and likely pathogenic by Invitae and Natera, Inc. Of the 3 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Thr1210Pro variant is pathogenic (PMID: 18395098, 22609309). In vitro functional studies provide some evidence that the p.Thr1210Pro variant may slightly impact protein function (PMID: 19101985, 22609309). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive BSEP deficiency. ACMG/AMP Criteria applied: PM3_strong, PP3_moderate, PM2_supporting, PS3_supporting (Richards 2015). |
| Natera, |
RCV001828705 | SCV002077882 | likely pathogenic | Progressive familial intrahepatic cholestasis type 2 | 2021-06-08 | no assertion criteria provided | clinical testing |