Submissions for variant NM_003742.4(ABCB11):c.1763C>T (p.Ala588Val)

gnomAD frequency: 0.00001  dbSNP: rs917981474

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000729841	SCV000857533	pathogenic	not provided	2018-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805834	SCV002050920	pathogenic	Progressive familial intrahepatic cholestasis	2021-12-02	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.1763C>T (p.Ala588Val) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248624 control chromosomes (gomAD). c.1763C>T has been reported in the literature in homozygous and compound heterozygous state in multiple individuals affected with Familial Intrahepatic Cholestasis (Walkowiak_2006, Strautnieks_2008, Zhang_2020, Hertel_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that although the variant didn't cause aberrant splicing in a minigene assay, however it resulted in the absence of protein product, indicating that the variant protein was rapidly degraded (Byrne_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000729841	SCV002301158	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 588 of the ABCB11 protein (p.Ala588Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with ABCB11-related conditions (PMID: 18395098, 34016879). This variant is also known as p.Ala558Val. ClinVar contains an entry for this variant (Variation ID: 594531). 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499353	SCV002810957	pathogenic	Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2	2024-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472263	SCV004204322	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2024-03-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742613	SCV005362174	pathogenic	ABCB11-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The ABCB11 c.1763C>T variant is predicted to result in the amino acid substitution p.Ala588Val. This variant has been reported in the homozygous state or heterozygous state with a second causative ABCB11 variant in patients with progressive familial intrahepatic cholestasis (Strautnieks et al. 2008. PubMed ID: 18395098; Zhang et al. 2020. PubMed ID: 33215027; Li. 2020. PubMed ID: 32808743; Hertel et al. 2021. PubMed ID: 34016879, Supplemental Table 3). We have also observed this variant in the compound heterozygous state with a second pathogenic variant in an affected patient (PreventionGenetics). In a protein expression study, the p.Ala588Val substitution resulted in complete absence of ABCB11 protein, which the authors suggested was due to decreased protein stability and subsequent rapid degradation (Byrne et al. 2009. PubMed ID: 19101985). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.