Submissions for variant NM_000443.4(ABCB4):c.526C>T (p.Arg176Trp)

gnomAD frequency: 0.00002  dbSNP: rs754287486

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414549	SCV000491319	pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20422496, 25755323, 31130284, 28587926, 28039895, 31625567, 31728073, 33915153, 34016879)
Eurofins Ntd Llc (ga)	RCV000414549	SCV000707313	likely pathogenic	not provided	2018-09-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331238	SCV001523234	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2020-02-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282130	SCV002570602	pathogenic	Progressive familial intrahepatic cholestasis	2022-07-20	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.526C>T (p.Arg176Trp) 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 4e-06 in 251280 control chromosomes (gnomAD). c.526C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Familial Intrahepatic Cholestasis (Goldschmidt_2016, Shagrani_2017, Sticova_2019, Fakhro_2019, Al-Hussaini_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000414549	SCV003440037	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 176 of the ABCB4 protein (p.Arg176Trp). This variant is present in population databases (rs754287486, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive progressive familial intrahepatic cholestasis (PMID: 20422496, 28039895, 31130284, 31625567, 33915153, 34016879, 35894240). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372802). 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. For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003227747	SCV003924339	pathogenic	Progressive familial intrahepatic cholestasis type 3	2023-05-08	criteria provided, single submitter	research
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001331238	SCV004801228	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2024-03-14	criteria provided, single submitter	research