ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1771C>T (p.Arg591Trp) (rs398123106)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498217 SCV000109788 pathogenic not provided 2013-06-04 criteria provided, single submitter clinical testing
GeneDx RCV000498217 SCV000589564 likely pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing The R591W variant has been reported in association with X-linked adrenoleukodystrophy (Takano et al., 1999; Guimarães et al., 2002; Jacob et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R591W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we consider this variant to be likely pathogenic.
Invitae RCV000808514 SCV000948624 pathogenic Adrenoleukodystrophy 2019-07-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 591 of the ABCD1 protein (p.Arg591Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with X-linked adrenoleukodystrophy (PMID: 10190819, 12175782, 24154795, 28503596). ClinVar contains an entry for this variant (Variation ID: 92321). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg591 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 7668254, 19129531, 22280810, 23566833), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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