Submissions for variant NM_003742.4(ABCB11):c.1445A>G (p.Asp482Gly)

gnomAD frequency: 0.00001  dbSNP: rs72549402

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000352712	SCV000342702	pathogenic	not provided	2018-08-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779284	SCV000915866	pathogenic	Progressive familial intrahepatic cholestasis type 2	2018-09-21	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ABCB11 c.1445A>G (p.Asp482Gly) variant has been identified in a homozygous state in 11 probands, in a compound heterozygous state in 18 probands, and in a heterozygous state in three probands (Strautnieks et al. 1998; Strautnieks et al. 2008; Giovannoni et al. 2015; Varma et al. 2016). The p.Asp482Gly variant was absent from 300 control chromosomes and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Strautnieks et al. (2008) showed that there was variability in the level of ABCB11 protein expression that did not correlate with genotype from normal to undetectable. Byrne et al. (2009) demonstrated that the p.Asp482Gly variant caused aberrant splicing with only 5% of normal splicing detected. The variant results in the introduction of 14 amino acids followed by a termination codon. Functional studies have shown that the variant protein is transcribed at comparable levels to the wild type protein and similarly located at the cell surface. However, the total protein expression level is significantly reduced to 2.5% and cell-surface protein expression to 5% of wild type suggesting that the variant reduces protein expression but does not impair trafficking to the membrane. Variant protein has been shown to be only partially glycosylated suggesting less stability. ATPase activity and bile acid transport of the p.Asp482Gly protein were shown to be comparable to wild type (Plass et al. 2004; Hayashi et al. 2005; Lam et al. 2007). Based on the collective evidence, the p.Asp482Gly variant is classified as pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000352712	SCV000949907	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 482 of the ABCB11 protein (p.Asp482Gly). This variant is present in population databases (rs72549402, gnomAD 0.004%). This missense change has been observed in individuals with ABCB11-related conditions (PMID: 9806540, 18395098, 26019043). ClinVar contains an entry for this variant (Variation ID: 288555). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB11 protein function. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 14672610, 19101985). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000352712	SCV001246018	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198579	SCV001369569	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2019-09-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,BP1.
Fulgent Genetics, Fulgent Genetics	RCV002494878	SCV002786254	pathogenic	Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2	2022-04-05	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000779284	SCV003935038	pathogenic	Progressive familial intrahepatic cholestasis type 2	2022-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001198579	SCV004207085	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2023-10-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000779284	SCV001459648	pathogenic	Progressive familial intrahepatic cholestasis type 2	2020-09-16	no assertion criteria provided	clinical testing