Submissions for variant NM_000033.4(ABCD1):c.1771C>T (p.Arg591Trp)

dbSNP: rs398123106

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000498217	SCV000109788	pathogenic	not provided	2013-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000498217	SCV000589564	likely pathogenic	not provided	2017-06-08	criteria provided, single submitter	clinical testing	The R591W variant has been reported in association with X-linked adrenoleukodystrophy (Takano et al., 1999; Guimarães et al., 2002; Jacob et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R591W 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. In summary, we consider this variant to be likely pathogenic.
Invitae	RCV000808514	SCV000948624	pathogenic	Adrenoleukodystrophy	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 591 of the ABCD1 protein (p.Arg591Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked adrenoleukodystrophy (PMID: 10190819, 12175782, 24154795, 28503596). ClinVar contains an entry for this variant (Variation ID: 92321). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg591 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7668254, 19129531, 22280810, 23566833). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000498217	SCV001473833	likely pathogenic	not provided	2019-12-11	criteria provided, single submitter	clinical testing	The ABCD1 c.1771C>T; p.Arg591Trp variant (rs398123106) is reported in the literature in individuals affected with X-linked adrenoleukodystrophy (X-ALD) (Guimaraes 2002, Jacob 2015, Takano 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 591 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Arg591Gln, p.Arg591Leu, p.Arg591Pro) have been reported in individuals with X-ALD and are considered disease-causing (Kemp 2001, Shimozawa 2011, Watkins 1995). Based on available information, the p.Arg591Trp variant is considered to be likely pathogenic. References: Guimaraes CP et al. Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene. Mol Genet Metab. 2002 May;76(1):62-7. Jacob R et al. Guillain Barre Syndrome in a Child With X-Linked Adrenoleukodystrophy. Child Neurol Open. 2015 Oct 6;2(4):2329048X15609606. Kemp S et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001 Dec;18(6):499-515. Shimozawa N et al. X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan. J Hum Genet. 2011 Feb;56(2):106-9. Takano H et al. Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy. Arch Neurol. 1999 Mar;56(3):295-300. Watkins PA et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995 Aug;57(2):292-301.
Revvity Omics, Revvity	RCV000498217	SCV002019416	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000808514	SCV002045838	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing