Submissions for variant NM_000443.4(ABCB4):c.3296A>G (p.Glu1099Gly)

gnomAD frequency: 0.00044  dbSNP: rs139042803

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734400	SCV000862539	uncertain significance	not provided	2018-07-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001161330	SCV001323196	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162879	SCV001324858	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000734400	SCV002117309	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1099 of the ABCB4 protein (p.Glu1099Gly). This variant is present in population databases (rs139042803, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cholestasis (PMID: 28733223). This variant is also known as E1106G. ClinVar contains an entry for this variant (Variation ID: 598093). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002485938	SCV002778193	uncertain significance	Progressive familial intrahepatic cholestasis type 3; Low phospholipid associated cholelithiasis; Cholestasis, intrahepatic, of pregnancy, 3	2022-02-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003938126	SCV004761350	uncertain significance	ABCB4-related condition	2023-11-07	criteria provided, single submitter	clinical testing	The ABCB4 c.3296A>G variant is predicted to result in the amino acid substitution p.Glu1099Gly. This variant has been reported in two families with low phospholipid associated choletithiasis and/or intrahepatic cholestasis of pregnancy; however, pathogenicity was not established (reported as NM_018849.2:c.3317G>A (p.E1106G) in Dröge et al 2017. PubMed ID: 28733223). This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-87035794-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.