Submissions for variant NM_003742.4(ABCB11):c.3691C>T (p.Arg1231Trp)

gnomAD frequency: 0.00002  dbSNP: rs766285158

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centogene AG - the Rare Disease Company	RCV001250138	SCV001424343	pathogenic	Familial intrahepatic cholestasis type 2		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568703	SCV003525076	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCB11 protein function. ClinVar contains an entry for this variant (Variation ID: 973516). This missense change has been observed in individuals with clinical features of ABCB11-related conditions (PMID: 16871584, 20232290, 25847299). This variant is present in population databases (rs766285158, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1231 of the ABCB11 protein (p.Arg1231Trp).
Revvity Omics, Revvity	RCV002568703	SCV003810566	likely pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462827	SCV004193389	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2024-03-27	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003984855	SCV004801253	pathogenic	Progressive familial intrahepatic cholestasis type 2	2024-03-14	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV003984855	SCV005042589	likely pathogenic	Progressive familial intrahepatic cholestasis type 2		criteria provided, single submitter	clinical testing	The missense variant c.3691C>Tp.Arg1231Trp in ABCB11 gene has been reported previously in compound heterozygous state in individuals with progressive familial intrahepatic cholestasis Davit-Spraul A, et al., 2010, Wang NL, et al., 2016. The variant is reported with 0.002% allele frequency in gnomAD Exomes and novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. However, experimental studies on the pathogenicity of the variant are not available. The amino acid Arginine at position 1231 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT.The amino acid change p.Arg1231Trp in ABCB11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV003984855	SCV005088838	pathogenic	Progressive familial intrahepatic cholestasis type 2	2020-07-17	criteria provided, single submitter	clinical testing	This variant was previously reported in patients with progressive familial intrahepatic cholestasis in compound heterozygous state [PMID: 18395098, 20232290, 16871584]. The clinical significance of the variant has not been reported in the literature; however, another missense variant (p.Arg1231Gln) affecting the same codon as of the identified variant has been reported as pathogenic in the ClinVar database.
Fulgent Genetics, Fulgent Genetics	RCV005029842	SCV005653412	likely pathogenic	Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2	2024-02-28	criteria provided, single submitter	clinical testing