Submissions for variant NM_003742.4(ABCB11):c.1907A>T (p.Glu636Val)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002741470	SCV003009472	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 636 of the ABCB11 protein (p.Glu636Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis (PMID: 34942279). ClinVar contains an entry for this variant (Variation ID: 1974573). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Glu636 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12717091, 34942279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004765560	SCV005380880	uncertain significance	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.1907A>T (p.Glu636Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain 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 247772 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1907A>T has been reported in the literature in individuals affected with Familial Intrahepatic Cholestasis (Minguez Rodriguez_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34942279). ClinVar contains an entry for this variant (Variation ID: 1974573). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004744436	SCV005343426	uncertain significance	ABCB11-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The ABCB11 c.1907A>T variant is predicted to result in the amino acid substitution p.Glu636Val. This variant, along with a second ABCB11 variant, has been reported in individuals with progressive familial intrahepatic cholestasis (Mínguez Rodríguez et al. 2022. PubMed ID: 34942279). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.