Submissions for variant NM_000443.4(ABCB4):c.217C>G (p.Leu73Val)

gnomAD frequency: 0.00074  dbSNP: rs8187788

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000416002	SCV000493299	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000416002	SCV000857260	uncertain significance	not provided	2018-06-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764724	SCV000895859	uncertain significance	Progressive familial intrahepatic cholestasis type 3; Low phospholipid associated cholelithiasis; Cholestasis, intrahepatic, of pregnancy, 3	2022-01-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001158470	SCV001320112	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.
Invitae	RCV000416002	SCV003255843	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the ABCB4 protein (p.Leu73Val). This variant is present in population databases (rs8187788, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with liver disease (PMID: 21119540, 23533021, 29238877). ClinVar contains an entry for this variant (Variation ID: 374521). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000416002	SCV004224031	uncertain significance	not provided	2022-03-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530518	SCV004747907	uncertain significance	ABCB4-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	The ABCB4 c.217C>G variant is predicted to result in the amino acid substitution p.Leu73Val. This variant has been reported in the heterozygous state in individuals with intrahepatic cholestasis, primary biliary cirrhosis, and cholelithiasis (Pauli-Magnus et al. 2004. PubMed ID: 14999697; Colombo et al. 2011. PubMed ID: 21119540; Anzivino et al. 2013. PubMed ID: 23022423; Poupon et al. 2013. PubMed ID: 23533021; Degiorgio et al. 2016. PubMed ID: 26324191; Vitale et al. 2018. PubMed ID: 29238877). This variant was also reported, along with a chain-terminating variant in ABCB4, in one individual with low-phospholipid-associated cholelithiasis syndrome (Poupon et al. 2013. PubMed ID: 23533021, Table 1). However, this variant is also reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.