Submissions for variant NM_000443.4(ABCB4):c.2144C>T (p.Thr715Ile)

gnomAD frequency: 0.00073  dbSNP: rs138773456

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724634	SCV000521298	uncertain significance	not provided	2018-07-05	criteria provided, single submitter	clinical testing	The T715I variant in the ABCB4 gene has been reported previously in progressive familialintrahepatic cholestasis type 3, in an affected individual who was heterozyous for the T715I variantand no second variant was identified (Degiorgio et al., 2007). Degiorgio et al. (2007) concluded thatthe effect of the T715I variant on the ABCB4 gene is not clear and further characterization of thisvariant is required. Although not present in the homozygous state, the NHLBI Exome SequencingProject reports T715I was observed in 10/8600 (0.12%) alleles from individuals of EuropeanAmerican background, indicating it may be a rare variant in this population. The T715I variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is not conserved. In silico analysis is inconsistent in its predictions as to whether or notthe variant is damaging to the protein structure/function. A missense variant in a nearby residue(F711S) has been reported in the Human Gene Mutation Database in association with progressivefamilial intrahepatic cholestasis (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. We interpret T715I as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000724634	SCV000700790	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000987908	SCV001137401	uncertain significance	Progressive familial intrahepatic cholestasis type 1	2023-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001161452	SCV001323334	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162981	SCV001324979	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.
Invitae	RCV000724634	SCV002199626	uncertain significance	not provided	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 715 of the ABCB4 protein (p.Thr715Ile). This variant is present in population databases (rs138773456, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with familial intrahepatic cholestasis (PMID: 17726488). ClinVar contains an entry for this variant (Variation ID: 381720). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCB4 function (PMID: 27256251). 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.
PreventionGenetics, part of Exact Sciences	RCV003409593	SCV004116108	uncertain significance	ABCB4-related condition	2024-02-28	criteria provided, single submitter	clinical testing	The ABCB4 c.2144C>T variant is predicted to result in the amino acid substitution p.Thr715Ile. This variant has been reported in an individual with familial progressive intrahepatic cholestasis (Degiorgio et al. 2007. PubMed ID: 17726488). An in vitro functional study reported that this variant did not significantly impact protein transport activity (Tables 1 and 2, Park et al. 2016. PubMed ID: 27256251). This variant is reported in 0.092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of uncertain and pathogenic (http://gnomad.broadinstitute.org/variant/7-87053289-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.