ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.823C>T (p.Arg275Trp) (rs782083931)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434855 SCV000525476 likely pathogenic not provided 2017-08-03 criteria provided, single submitter clinical testing The R275W variant in the ABCD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R275W 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. Missense variants in nearby residues (E271K, A273E, R274P, K276E, G277R, G277W, G277E, L279P, R280C, R280L) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy or with adrenomyeloneuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R275W variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507685 SCV000602346 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing
Invitae RCV000695726 SCV000824241 uncertain significance Adrenoleukodystrophy 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 275 of the ABCD1 protein (p.Arg275Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs782083931, ExAC 0.006%). This variant has not been reported in the literature in individuals with ABCD1-related disease. This variant has been reported to segregate with disease in at least one family, although details are not provided ( ClinVar contains an entry for this variant (Variation ID: 384589). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000695726 SCV000891168 likely pathogenic Adrenoleukodystrophy 2017-09-19 criteria provided, single submitter clinical testing

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