Submissions for variant NM_003742.4(ABCB11):c.1763C>G (p.Ala588Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003664110	SCV004377128	likely pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ala588 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18395098, 34016879). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 588 of the ABCB11 protein (p.Ala588Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ABCB11-related conditions. 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. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005254848	SCV005907496	uncertain significance	Progressive familial intrahepatic cholestasis type 2	2025-01-27	criteria provided, single submitter	curation	The p.Ala588Gly variant in ABCB11 has not been previously reported in the literature in individuals with BSEP deficiency, and has been identified in 0.001% (1/74926) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs917981474). 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: 2782675) and has been interpreted as likely pathogenic by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic or pathogenic variants, resulting in a different amino acid change at the same position, p.Ala588Val and p.Ala588Pro, have been reported in association with disease in the literature or ClinVar, supporting that a change at this position may not be tolerated (PMID: 36046230, 27050426/Variation ID: 594531). In summary, the clinical significance of the p.Ala588Gly variant is uncertain. ACMG/AMP Criteria applied: PM5, PP3, PM2_supporting (Richards 2015).