ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1202G>A (p.Arg401Gln) (rs128624219)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012052 SCV000947088 pathogenic Adrenoleukodystrophy 2019-02-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 401 of the ABCD1 protein (p.Arg401Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with X-linked adrenoleukodystrophy (PMID: 8566952, 15811009, 21966424, 23419472 26388597). This variant is also known as G1588A in the literature. ClinVar contains an entry for this variant (Variation ID: 11300). 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.Arg401 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 10190819, 22479560), 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.
Johns Hopkins Genomics,Johns Hopkins University RCV000012052 SCV000992347 pathogenic Adrenoleukodystrophy 2019-04-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001636 SCV001159134 pathogenic not specified 2018-09-21 criteria provided, single submitter clinical testing The ABCD1 c.1202G>A; p.Arg401Gln variant (rs128624219) has been described in several individuals and families affected with X-linked adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN; see link to ALD ABCD1 database and references therein, Kemp 2001, Krasemann 1996, Kumar 2011, Shimozawa 2011, Watkins 1995). It contains an entry in ClinVar (Variation ID: 11300), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 401 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, other variants at this codon (c.1201C>T; p.Arg401Trp and c.1201C>G; p.Arg401Gly) have been described in several individuals with ALD and are considered pathogenic (see link to ALD ABCD1 database and references therein, Shimozawa 2011). Based on available information, this variant is considered pathogenic. References: ALD ABCD1 database: 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. Krasemann E et al. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996 Feb;97(2):194-7. Kumar N et al. Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India. PLoS One. 2011;6(9):e25094. Shimozawa N et al. X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan. J Hum Genet. 2011 Feb;56(2):106-9. Watkins P et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995 Aug;57(2):292-301.
OMIM RCV000012052 SCV000032286 pathogenic Adrenoleukodystrophy 1994-10-01 no assertion criteria provided literature only

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