Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Neuberg Centre For Genomic Medicine, |
RCV000007696 | SCV005382437 | pathogenic | Progressive familial intrahepatic cholestasis type 1 | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense c.1367C>T(p.Thr456Met) variant in ATP8B1 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with progressive familial intrahepatic cholestasis (Mínguez Rodríguez B, et al., 2022; Mizutani A, et al., 2020; Oya Y, et al., 2017; Alvarez L, et al., 2004). The p.Thr456Met variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 456 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. |
| Labcorp Genetics |
RCV005089202 | SCV005836884 | likely pathogenic | not provided | 2024-01-25 | 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 456 of the ATP8B1 protein (p.Thr456Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ATP8B1-related conditions (PMID: 15239083, 33666275). ClinVar contains an entry for this variant (Variation ID: 7273). 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 ATP8B1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 19381753). 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. |
| OMIM | RCV000007696 | SCV000027897 | pathogenic | Progressive familial intrahepatic cholestasis type 1 | 2004-10-15 | no assertion criteria provided | literature only |