ClinVar Miner

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

dbSNP: rs1382100120
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 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
PreventionGenetics, part of Exact Sciences RCV003941221 SCV004751809 likely pathogenic ABCB11-related disorder 2023-12-01 criteria provided, single submitter 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003152782 SCV004801256 uncertain significance Progressive familial intrahepatic cholestasis type 2 2024-03-14 criteria provided, single submitter research

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