ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.488G>A (p.Arg163His) (rs1057517954)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414525 SCV000491176 likely pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing The R163H variant in the ABCD1 gene has been reported previously in association with X-linked adrenoleukodystrophy in a symptomatic female carrier (Ligtenberg et al., 1995). The R163H variant was not observed in approximately 6,500 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 R163H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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 the same and nearby residues (L158P, L160P, S161P, R163P, R163L, R163G) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R163H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000699535 SCV000828250 likely pathogenic Adrenoleukodystrophy 2019-02-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 163 of the ABCD1 protein (p.Arg163His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with X-linked adrenoleukodystrophy (PMID: 7825602). ClinVar contains an entry for this variant (Variation ID: 372736). 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. Other missense substitutions at this codon (p.Arg163Pro, p.Arg163Leu, p.Arg163Gly) have been reported in individuals affected with X-linked adrenoleukodystrophy (PMID: 10980309, 25324868, 26227820). 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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