ClinVar Miner

Submissions for variant NM_018849.3(ABCB4):c.959C>T (p.Ser320Phe) (rs72552778)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000190560 SCV000245567 uncertain significance Progressive familial intrahepatic cholestasis 3 2014-08-22 criteria provided, single submitter 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.
Illumina Clinical Services Laboratory,Illumina RCV000014688 SCV000470156 pathogenic Cholecystitis 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 likely pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing The S320F variant has been reported in association with progressive familial intrahepatic cholestasis type 3 as well as intrahepatic cholestasis of pregnancy (Degiorgio et al., 2007; Bacq et al., 2009). The S320F variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S320F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498517 SCV000706335 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing
OMIM RCV000014688 SCV000034943 pathogenic Cholecystitis 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

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