ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.880G>A (p.Ala294Thr) (rs1131691954)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492856 SCV000583219 likely pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing The A294T variant in the ABCD1 gene has been reported previously in one individual with adrenomyeloneuropathy (Feigenbaum et al., 1996). The A294T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A294T 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. In addition, 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. A missense variant at the same residue (A294V) and in nearby residues (S290W, E291K, E291D, Y296H, Y296C, G298S, G298V, G298D, G298R) have been reported in the Human Gene Mutation Database in association with adrenomyeloneuropathy and adrenoleukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A294T as a likely pathogenic variant.
Invitae RCV000686131 SCV000813634 uncertain significance Adrenoleukodystrophy 2018-04-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 294 of the ABCD1 protein (p.Ala294Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with adrenomyeloneuropathy (PMID: 8651290). ClinVar contains an entry for this variant (Variation ID: 430421). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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