ClinVar Miner

Submissions for variant NM_003742.4(ABCB11):c.3669G>C (p.Glu1223Asp)

gnomAD frequency: 0.00002  dbSNP: rs199649780
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV003473542 SCV004203027 likely pathogenic Benign recurrent intrahepatic cholestasis type 2 2024-03-27 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003480901 SCV004224989 uncertain significance not provided 2023-02-23 criteria provided, single submitter clinical testing PM2, PS4_moderate
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV005253677 SCV005907422 uncertain significance Progressive familial intrahepatic cholestasis type 2 2025-01-23 criteria provided, single submitter curation The p.Glu1223Asp variant in ABCB11 has been reported in at least three individuals with BSEP deficiency (PMID: 20683201, 34016879, 29992621; doi.org:10.33612:diss.13343025), and has been identified in 0.008% (92/1179784) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199649780). 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: 812747) and has been interpreted as pathogenic/likely pathogenic by NIHR Bioresource Rare Diseases (University of Cambridge) and Baylor Genetics, and as a variant of uncertain significance by Mayo Clinic Laboratories. Of the three affected individuals, two were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant with unknown phase, which increases the likelihood that the p.Glu1223Asp variant is pathogenic (Variation ID: 6590; doi.org:10.33612:diss.133430251). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3 (Richards 2015).
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003551 SCV001161895 pathogenic Cholestasis, intrahepatic, of pregnancy, 3 no assertion criteria provided research

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