Submissions for variant NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)

gnomAD frequency: 0.00018  dbSNP: rs72552778

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000014688	SCV000470156	pathogenic	Low phospholipid associated cholelithiasis	2017-04-28	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ABCB4 c.959C>T (p.Ser320Phe) missense variant has been identified in a homozygous state in four patients with intrahepatic cholestasis of pregnancy, in a homozygous state in one patient with progressive familial intrahepatic cholestasis type 3, in a homozygous state in one patient with low phospholipid associated cholelithiasis, and in a compound heterozygotes state in seven patients with progressive familial intrahepatic cholestasis type 3 (Rosmorduc et al. 2001; Rosmorduc et al. 2003; Pauli-Magnus et al. 2004; Keitel et al. 2006; Degiorgio et al. 2007; Colombo et al. 2011; Oliveira et al. 2016). The p.Ser320Phe variant was absent from 630 controls and is reported at a frequency of 0.00020 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transfection of the p.Ser320Phe variant into HEK293T and MDCK-II cells showed that the variant protein had similar activity as compared to wild type, however the expression levels were slightly reduced (Kim et al. 2013; Andress et al. 2014; Gordo-Gilart et al. 2016). Based on the evidence, the p.Ser320Phe variant is classified as pathogenic for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000498517	SCV000589676	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	One in vitro study showed decreased transport activity, while another showed reduced protein expression but normal protein function (PMID: 26153658, 24381502); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19490418, 17562004, 26699824, 23533021, 24381502, 22331132, 11313316, 19840255, 17786139, 19584064, 15077010, 16890614, 17726488, 21119540, 26324191, 28776642, 29761167, 24806754, 28733223, 30487145, 31538484, 32793533, 32581362, 35288833, 37822304, 34376370, 33258288, 36330364, 33390354, 32893960, 32650689, 26153658)
Eurofins Ntd Llc (ga)	RCV000498517	SCV000706335	pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000498517	SCV001962061	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000014688	SCV002517498	pathogenic	Low phospholipid associated cholelithiasis	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498517	SCV003457569	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the ABCB4 protein (p.Ser320Phe). This variant is present in population databases (rs72552778, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of autosomal recessive progressive familial intrahepatic cholestasis type 3 (PMID: 11313316, 32893960). ClinVar contains an entry for this variant (Variation ID: 13690). 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. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 24806754). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226159	SCV003922668	pathogenic	Progressive familial intrahepatic cholestasis	2023-03-02	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.959C>T (p.Ser320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251176 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00016 vs 0.0022), allowing no conclusion about variant significance. c.959C>T has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (example: Rosmmorduc_2001 and de Vries_2020). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042051	SCV005674288	likely pathogenic	Progressive familial intrahepatic cholestasis type 3; Low phospholipid associated cholelithiasis; Cholestasis, intrahepatic, of pregnancy, 3	2024-05-22	criteria provided, single submitter	clinical testing
OMIM	RCV000014688	SCV000034943	pathogenic	Low phospholipid associated cholelithiasis	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000033065	SCV000056845	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2009-10-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190560	SCV000245567	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2014-08-22	flagged submission	clinical testing	The Ser320Phe variant in ABCB4 has been reported in 9 heterozygous, 6 homozygous, and 4 compound heterozygous individuals with cholestatic liver disease (Andress 2014, Poupon 2013, Wendum 2012, Bacq 2009, Degiorgio 2007, Colombo 2011, Rosmorduc 2001, Pauli-Magnus 2004, Zimmer 2009, Keitel 2006). This variant has been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72552778). Computational analyses (biochemical amino acid properties, conservation and PolyPhen2) do not provide strong support for or against an impact to the protein. In vitro assays suggest the Ser320Phe variant may affect protein function (Andress 2014, Kim 2013); however these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Ser320Phe variant is uncertain.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000033065	SCV001161919	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3		no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000498517	SCV001931835	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000498517	SCV001968202	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532350	SCV004115331	likely pathogenic	ABCB4-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The ABCB4 c.959C>T variant is predicted to result in the amino acid substitution p.Ser320Phe. This variant has been reported in the homozygous or compound heterozygous state in several individuals with cholestasis phenotypes (see for example, Rosmorduc et al. 2001. PubMed ID: 11313316; Keitel et al. 2006. PubMed ID: 16890614; Degiorgio et al. 2007 PubMed ID: 17726488). In vitro functional assessment has been inconclusive (Kim et al. 2013. PubMed ID: 24381502; Andress et al. 2014. PubMed ID: 24806754; Gordo-Gilart et al. 2015. PubMed ID: 26153658). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.