ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1771C>T (p.Arg591Trp) (rs398123106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 591 of the ABCD1 protein (p.Arg591Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with X-linked adrenoleukodystrophy (PMID: 10190819, 12175782, 24154795, 28503596). ClinVar contains an entry for this variant (Variation ID: 92321). 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 disrupts the p.Arg591 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 7668254, 19129531, 22280810, 23566833), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287176 SCV001473833 likely pathogenic none 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.

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