Submissions for variant NM_003742.4(ABCB11):c.2012-8T>G

gnomAD frequency: 0.00006  dbSNP: rs769910565

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000339283	SCV000337332	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763464	SCV000894241	pathogenic	Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779283	SCV000915865	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2018-10-23	criteria provided, single submitter	clinical testing	The ABCB11 c.2012-8T>G variant has been identified in a compound heterozygous state in at least six probands and in a heterozygous state in one proband in whom a second variant was not identified, all with familial intrahepatic cholestasis (Knisely et al. 2006; Siebold et al. 2010; Strautnieks et al. 2008; Grammatikopoulos et al. 2015). The c.2012-8T>G variant was absent from 500 control individuals and is reported at a frequency of 0.000056 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.2012-8T>G variant is classified as likely pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000339283	SCV000956198	pathogenic	not provided	2024-03-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 16 of the ABCB11 gene. It does not directly change the encoded amino acid sequence of the ABCB11 protein. This variant is present in population databases (rs769910565, gnomAD 0.006%). This variant has been observed in individuals with ABCB11-related conditions (PMID: 18395098). ClinVar contains an entry for this variant (Variation ID: 284637). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000339283	SCV004035430	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss of function (Strautnieks et al., 2008); This variant is associated with the following publications: (PMID: 16871584, 32581362, 35894240, 24402531, 20583290, 24231640, 18395098)
PreventionGenetics, part of Exact Sciences	RCV003401248	SCV004105719	pathogenic	ABCB11-related disorder	2023-08-04	criteria provided, single submitter	clinical testing	The ABCB11 c.2012-8T>G variant is predicted to interfere with splicing. This variant was previously reported in the compound heterozygous state in individuals who presented with familial intrahepatic cholestasis (Knisely et al. 2006. PubMed ID: 16871584, reported as IVS16-8T>G; Siebold et al. 2010. PubMed ID: 20583290; Strautnieks et al. 2008. PubMed ID: 18395098). In vitro analysis from one study indicated that this variant led to skipping of exon 17 and a resulting frameshift with premature protein termination (Knisely et al. 2006. PubMed ID: 16871584). This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-169825008-A-C) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/284637/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003463756	SCV004198059	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2024-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492026	SCV004240833	pathogenic	Progressive familial intrahepatic cholestasis	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.2012-8T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' cryptic acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 244560 control chromosomes. c.2012-8T>G has been reported in the literature at a compound heterozygous state along with difference pathogenic variants in multiple individuals affected with Familial Intrahepatic Cholestasis (examples, Knisely_2006, Strautnieks_2008). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on splicing, however, detailed information of such results are not available for an independent evaluation (Strautnieks_2008). The following publications have been ascertained in the context of this evaluation (PMID: 16871584, 18395098). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003555	SCV001161899	likely pathogenic	Cholestasis, intrahepatic, of pregnancy, 3		no assertion criteria provided	research
Natera, Inc.	RCV000779283	SCV002077899	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2021-01-22	no assertion criteria provided	clinical testing