Submissions for variant NM_003742.4(ABCB11):c.677C>T (p.Ser226Leu)

dbSNP: rs1382100120

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001958485	SCV002219305	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 226 of the ABCB11 protein (p.Ser226Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis (PMID: 20232290, 20414253, 21404481, 27239116). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1446326). 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 not expected to disrupt ABCB11 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001958485	SCV003824332	uncertain significance	not provided	2021-10-26	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV003152782	SCV003841546	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: VCV001446326). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20232290). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401948	SCV004122504	pathogenic	Progressive familial intrahepatic cholestasis	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.677C>T (p.Ser226Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246750 control chromosomes (gnomAD). c.677C>T has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (Davit-Spraul_2010, Shapiro_2010, Li_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20232290, 20414253, 32808743). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003464279	SCV004213895	likely pathogenic	Benign recurrent intrahepatic cholestasis type 2	2023-04-04	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003152782	SCV004801256	uncertain significance	Progressive familial intrahepatic cholestasis type 2	2024-03-14	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003941221	SCV004751809	likely pathogenic	ABCB11-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The ABCB11 c.677C>T variant is predicted to result in the amino acid substitution p.Ser226Leu. This variant was reported in the homozygous or compound heterozygous state in multiple individuals with progressive familial intrahepatic cholestasis (Davit-Spraul et al. 2010. PubMed ID: 20232290; Li et al. 2020. PubMed ID: 32808743; Park et al. 2016. PubMed ID: 27239116; Table S3B, Neřoldová et al. 2023. PubMed ID: 37471416). This variant was also described, along with a second heterozygous variant, in two siblings with cholestasis (Shapiro et al. 2010. PubMed ID: 20414253). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. In summary, we classify this variant as likely pathogenic.