Submissions for variant NM_003742.4(ABCB11):c.3094G>C (p.Gly1032Arg)

dbSNP: rs2105891596

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002019629	SCV002278496	likely pathogenic	not provided	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1032 of the ABCB11 protein (p.Gly1032Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with progressive familial intrahepatic cholestasis type 2 (PMID: 28733223, 28839429). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1498315). 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. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 28839429). 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	RCV005254009	SCV005907448	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2025-01-23	criteria provided, single submitter	curation	The p.Gly1032Arg variant in ABCB11 has been reported, in the compound heterozygous state, in 1 individual with BSEP deficiency (PMID: 28839429; Variation ID: 1410817), and has been identified in 0.0002% (2/1179760) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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: 1498315) and has been interpreted as likely pathogenic by Invitae. In vitro functional studies provide some evidence that the p.Gly1032Arg variant may slightly impact protein function (PMID: 28839429). 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. ACMGAMP Criteria applied: PP3_moderate, PM2_supporting, PM3, PS3_supporting (Richards 2015).