ClinVar Miner

Submissions for variant NM_003742.4(ABCB11):c.499G>A (p.Ala167Thr)

gnomAD frequency: 0.00001  dbSNP: rs139641883
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001985500 SCV002226850 pathogenic not provided 2023-06-28 criteria provided, single submitter clinical testing This missense change has been observed in individuals with progressive familial intrahepatic cholestasis (PMID: 19845854, 20232290, 24627769, 28119944). 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) 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 ABCB11 protein function. ClinVar contains an entry for this variant (Variation ID: 1446335). This variant is present in population databases (rs139641883, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 167 of the ABCB11 protein (p.Ala167Thr).
Baylor Genetics RCV003464280 SCV004214006 pathogenic Benign recurrent intrahepatic cholestasis type 2 2023-08-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003911123 SCV004723732 likely pathogenic ABCB11-related disorder 2024-02-13 criteria provided, single submitter clinical testing The ABCB11 c.499G>A variant is predicted to result in the amino acid substitution p.Ala167Thr. This variant was reported in the homozygous and compound heterozygous states in at least five unrelated individuals with intrahepatic cholestasis (Liu et al. 2009. PubMed ID: 19845854; Davit-Spraul et al. 2010. PubMed ID: 20232290; McKay et al. 2013. PubMed ID: 24627769; Collyer et al. 2016. PubMed ID: 28119944; Wang et al. 2022. PubMed ID: 35257483). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Different substitutions at this amino acid position (p.Ala167Val, p.Ala167Glu) have also been reported in individuals with intrahepatic cholestasis (Byrne et al. 2009. PubMed ID: 19101985; Li et al. 2020. PubMed ID: 32808743). Taken together, the c.499G>A (p.Ala167Thr) variant is interpreted as likely pathogenic.

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