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

dbSNP: rs1569541088

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001057299	SCV001221784	likely pathogenic	Adrenoleukodystrophy	2019-01-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. 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. This variant has been observed in an individual affected with X-linked adrenoleukodystrophy (Invitae). 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.
PreventionGenetics, part of Exact Sciences	RCV003396694	SCV004110680	uncertain significance	ABCD1-related condition	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.