ClinVar Miner

Submissions for variant NM_003742.4(ABCB11):c.2495G>A (p.Arg832His)

dbSNP: rs376255350
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000594076 SCV002222241 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 832 of the ABCB11 protein (p.Arg832His). This variant is present in population databases (rs376255350, gnomAD 0.0009%). This missense change has been observed in individual(s) with progressive familial intrahepatic cholestasis (PMID: 28425419). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499070). 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%. This variant disrupts the p.Arg832 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16641580, 18395098, 27114171, 28733223). 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.
Baylor Genetics RCV003465341 SCV004214264 pathogenic Benign recurrent intrahepatic cholestasis type 2 2024-03-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004579556 SCV005062126 likely pathogenic Progressive familial intrahepatic cholestasis 2024-03-27 criteria provided, single submitter clinical testing Variant summary: ABCB11 c.2495G>A (p.Arg832His) results in a non-conservative amino acid change in 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 248566 control chromosomes (gnomAD). c.2495G>A has been reported in the literature in individuals affected with progressive familial intrahepatic cholestasis, cholestasis of undefined etiology and transient neonatal cholestasis (examples: Matt_2010, Waisbourd-Zinman_2017, Li_2020, Al-Hussaini_2021, Al-Hussaini_2021, Hertel_2021). A different variant affecting this residue has been classified pathogenic by our lab (c.2494C>T, p.Arg832Cys), suggesting this variant may be clinically significant. These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33915153, 34016879, 37471416, 20683201, 28425419). ClinVar contains an entry for this variant (Variation ID: 499070). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Eurofins Ntd Llc (ga) RCV000594076 SCV000704376 uncertain significance not provided 2016-12-05 flagged submission clinical testing

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