ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.565C>T (p.Arg189Trp) (rs1131691916)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493301 SCV000583137 likely pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The R189W variant in the ABCD1 gene has been reported previously in at least two individuals with adrenoleukodystrophy, including one individual with Addison disease and one with adrenomyeloneuropathy (Lachtermacher et al., 2000; Coll et al., 2005). The R189W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R189W variant 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. R189W is reported as pathogenic variant in the ALD Database, as is another missense variant at the same position, supporting the functional importance of this residue. Additionally, missense variants in nearby residues (L190P, D194H, and D194N) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy (Stenson et al., 2014). We interpret R189W as a likely pathogenic variant.
Invitae RCV000633486 SCV000754719 likely pathogenic Adrenoleukodystrophy 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 189 of the ABCD1 protein (p.Arg189Trp). 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 reported in individuals affected with adrenoleukodystrophy in the literature (PMID: 10737980, 15811009) and in the ALD database (http://adrenoleukodystrophy.info/). ClinVar contains an entry for this variant (Variation ID: 430349). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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