ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1165C>T (p.Arg389Cys)

gnomAD frequency: 0.00001  dbSNP: rs128624215
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761215 SCV000891169 likely pathogenic Adrenoleukodystrophy 2018-04-17 criteria provided, single submitter clinical testing
Invitae RCV000761215 SCV001418216 likely pathogenic Adrenoleukodystrophy 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 389 of the ABCD1 protein (p.Arg389Cys). This variant is present in population databases (rs128624215, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary spastic paraplegia and/or adrenoleukodystrophy (PMID: 15800013, 22280810, 30564185, 32307584). ClinVar contains an entry for this variant (Variation ID: 623115). 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 ABCD1 protein function. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581394, 7825602, 8566952, 15811009, 22479560, 24719134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab RCV000761215 SCV002045764 likely pathogenic Adrenoleukodystrophy 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000761215 SCV003922520 likely pathogenic Adrenoleukodystrophy 2023-03-31 criteria provided, single submitter clinical testing Variant summary: ABCD1 c.1165C>T (p.Arg389Cys) 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 9e-06 in 111465 control chromosomes (gnomAD v3.1.2). c.1165C>T has been reported in the literature in several hemizygous individuals affected with Adrenoleukodystrophy and Adrenomyeloneuropathy (e.g. Asheuer_2005, Salsano_2012, D'Amore_2018, Benzoni_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and four as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000761215 SCV002084628 uncertain significance Adrenoleukodystrophy 2021-06-02 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein RCV000761215 SCV002583446 likely pathogenic Adrenoleukodystrophy 2022-05-02 no assertion criteria provided clinical testing

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