chr2-168972025-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_003742.4(ABCB11):c.1460G>A(p.Arg487His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,612,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487C) has been classified as Likely 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB11 | NM_003742.4 | c.1460G>A | p.Arg487His | missense_variant | 14/28 | ENST00000650372.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB11 | ENST00000650372.1 | c.1460G>A | p.Arg487His | missense_variant | 14/28 | NM_003742.4 | P1 | ||
ABCB11 | ENST00000439188.1 | c.8G>A | p.Arg3His | missense_variant, NMD_transcript_variant | 1/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000132 AC: 20AN: 152006Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000928 AC: 23AN: 247784Hom.: 0 AF XY: 0.0000744 AC XY: 10AN XY: 134412
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1460544Hom.: 0 Cov.: 32 AF XY: 0.0000606 AC XY: 44AN XY: 726556
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 14, 2021 | PP3, PM2, PM3_strong, PM5, PS3_moderate - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 487 of the ABCB11 protein (p.Arg487His). This variant is present in population databases (rs188824058, gnomAD 0.02%). This missense change has been observed in individual(s) with chronic cholestasis (PMID: 12717091, 27050426). 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: 290081). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg487 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been observed in individuals with ABCB11-related conditions (PMID: 12717091, 18395098, 27050426), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 07, 2023 | - - |
Progressive familial intrahepatic cholestasis type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2020 | The ABCB11 c.1460G>A p.(Arg487His) missense has been identified in individuals with a phenotype consistent with progressive familial intrahepatic cholestasis (Goto et al. 2003; Strautnieks et al. 2008; Smith Jericho et al. 2015; Togawa et al. 2016; Wang et al. 2016; Dröge et al. 2017; Nakano et al. 2019; Liu et al. 2020). The p.(Arg487His) variant is reported at a frequency of 0.0001726 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). The variant is located within the conserved nucleotide binding domain of the protein (Wang et al. 2020). Ectopic overexpression of the p.(Arg487His) variant in the liver cell line HepG2, resulted in mislocalisation within the endoplasmic reticulum (ER) when compared to the wild type control which localized to the bile canaliculus (Nakano et al. 2019). Expression studies in HEK293 cells indicated that whilst the majority of the mutant protein was retained in the ER, the portion of the p.(Arg487His) variant protein which did localize to the cell membrane, retained ABCB11 ATP-dependent transporter activity (Nakano et al. 2019). Based on the available evidence the c.1460G>A p.(Arg487His) variant is classified as pathogenic for progressive familial intrahepatic cholestasis. - |
Likely pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Nov 30, 2023 | - - |
ABCB11-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 31, 2022 | The ABCB11 c.1460G>A variant is predicted to result in the amino acid substitution p.Arg487His. This variant has been reported in the compound heterozygous state with other pathogenic ABCB11 variants in multiple individuals with autosomal recessive familial progressive intrahepatic cholestasis (Goto et al. 2003. PubMed ID: 12717091; Dröge et al. 2017. PubMed ID: 28733223; Turro et al. 2020. PubMed ID: 32581362; Li et al. 2020. PubMed ID: 32808743) Two other missense changes at the same amino acid position have also been reported in individuals with ABCB11-related disorders (p.Arg487Cys, p.Arg487Pro; Human Gene Mutation Database). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-169828535-C-T). This variant is interpreted as likely pathogenic. - |
Cholestasis, intrahepatic, of pregnancy, 3 Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2023 | - - |
Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Progressive familial intrahepatic cholestasis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2021 | Variant summary: ABCB11 c.1460G>A (p.Arg487His) results in a non-conservative amino acid change located in the ABC transporter-like, 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 9.3e-05 in 247784 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCB11 causing Familial Intrahepatic Cholestasis (9.3e-05 vs 0.0022), allowing no conclusion about variant significance. c.1460G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Familial Intrahepatic Cholestasis (example, Goto_2003, Li Wang_2016, Togawa_2016, Liu_2018, Ting Li_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=3; VUS, n=1). At-least one submitter cites overlapping but not identical evidence utilized in the context of this evaluation. 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