Submissions for variant NM_003742.4(ABCB11):c.2178+2T>C

dbSNP: rs1693198121

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centogene AG - the Rare Disease Company	RCV001250140	SCV001424345	likely pathogenic	Familial intrahepatic cholestasis type 2		criteria provided, single submitter	clinical testing
Rolfs Rare Disease Consulting, Rolfs Consulting Und Verwaltungs GmbH	RCV003485694	SCV004232466	pathogenic	Progressive familial intrahepatic cholestasis type 2	2019-01-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003485694	SCV005907478	pathogenic	Progressive familial intrahepatic cholestasis type 2	2025-01-24	criteria provided, single submitter	curation	The c.2178+2T>C variant in ABCB11 has been reported, in the homozygous state, in 1 individual with BSEP deficiency (PMID: 33083013), and has been identified in 0.00009% (1/1145270) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1693198121). 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: 973518) and has been interpreted as pathogenic by Rolfs Rare Disease Consulting and likely pathogenic by Centogene AG. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ABCB11 gene is an established disease mechanism in autosomal recessive BSEP deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive BSEP deficiency. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015).