ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1534G>C (p.Gly512Arg)

dbSNP: rs1569541088
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001057299 SCV001221784 likely pathogenic Adrenoleukodystrophy 2019-01-20 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Gly512 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 7581394, 26523528, 11248239, 11336405, 19496984), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This sequence change replaces glycine with arginine at codon 512 of the ABCD1 protein (p.Gly512Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with X-linked adrenoleukodystrophy (Invitae). 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.
PreventionGenetics, part of Exact Sciences RCV003396694 SCV004110680 uncertain significance ABCD1-related disorder 2023-02-06 criteria provided, single submitter clinical testing The ABCD1 c.1534G>C variant is predicted to result in the amino acid substitution p.Gly512Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, other variants at impacting the same amino acid (p.Gly512Ser, p.Gly512Cys, and p.Gly512Asp) have been documented in patients with adrenoleukodystrophy (Baker et al. 2022. PubMed ID: 35645283; Neumann et al. 2001. PubMed ID: 11336405; Awaya et al. 2011. PubMed ID: 19496984). Although we suspect that this variant may be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.

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