NM_003742.4:c.1763C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003742.4(ABCB11):c.1763C>T(p.Ala588Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_003742.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151944Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248624Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134876
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460860Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726736
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151944Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74186
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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. -
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ABCB11-related disorder Pathogenic:1
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. -
Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1
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Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 Pathogenic:1
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Progressive familial intrahepatic cholestasis Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at