ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1876G>A (p.Ala626Thr) (rs1557055316)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699538 SCV000828253 pathogenic Adrenoleukodystrophy 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 626 of the ABCD1 protein (p.Ala626Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with the cerebral form of adrenoleukodystrophy (CALD) (PMID: 21700483). This variant has also been reported in individuals affected with CALD and adrenomyeloneuropathy (AMN), and has been reported to segregate with disease in an affected family (PMID: 7581394, 7668254). ClinVar contains an entry for this variant (Variation ID: 576910). Experimental studies in patient fibroblasts have found that this missense variant leads to reduced ABCD1 protein expression (PMID: 7668254). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002086 SCV001159930 likely pathogenic not specified 2018-08-28 criteria provided, single submitter clinical testing The ABCD1 c.1876G>A; p.Ala626Thr variant is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (Kemp 2001, Park 2018, Watkins 1995). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein show undetectable protein levels (Kemp 2001). The alanine at codon 626 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala626Thr variant is considered to be likely pathogenic. References: 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. Park JS et al. Spastic paraparesis caused by X-linked adrenoleukodystrophy mimicking vacuolar myelopathy in a human immunodeficiency virus patient: A case report. Medicine (Baltimore). 2018 May;97(20):e10756. 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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