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: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001985500 SCV002226850 pathogenic not provided 2024-04-10 criteria provided, single submitter clinical testing 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). This variant is present in population databases (rs139641883, gnomAD 0.003%). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis (PMID: 19845854, 20232290, 24627769, 28119944). ClinVar contains an entry for this variant (Variation ID: 1446335). 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003464280 SCV004214006 pathogenic Benign recurrent intrahepatic cholestasis type 2 2024-03-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587264 SCV005075804 pathogenic Progressive familial intrahepatic cholestasis 2024-04-03 criteria provided, single submitter clinical testing Variant summary: ABCB11 c.499G>A (p.Ala167Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane 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 1.2e-05 in 247276 control chromosomes. c.499G>A has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (Davit-Spraul_2010, Li_2020, Liu_2010, McKay_2013, Collyer_2016, Wang_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28119944, 20232290, 32808743, 19845854, 24627769, 35257483). ClinVar contains an entry for this variant (Variation ID: 1446335). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001985500 SCV005413520 pathogenic not provided 2023-11-03 criteria provided, single submitter clinical testing PP3, PP4, PM2_moderate, PM3_strong, PS4_moderate
Fulgent Genetics, Fulgent Genetics RCV005016921 SCV005652961 likely pathogenic Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2 2024-04-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003911123 SCV004723732 likely pathogenic ABCB11-related disorder 2024-02-13 no assertion criteria provided 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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