ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1553G>A (p.Arg518Gln) (rs398123102)

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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 RCV000723540 SCV000109784 pathogenic not provided 2012-10-08 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health: University of Minnesota RCV000077955 SCV000840437 pathogenic Adrenoleukodystrophy 2017-04-26 criteria provided, single submitter clinical testing
Invitae RCV000077955 SCV001207477 pathogenic Adrenoleukodystrophy 2019-04-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 518 of the ABCD1 protein (p.Arg518Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs398123102, ExAC 0.002%). This variant has been reported in the literature in an individual with ABCD1-related conditions (PMID: 21068741, 23566833, 15811009, 10190819, 16087056, 12175782, 26260157, 23419472), and has been observed to be de novo in individuals affected with ABCD1-related conditions (PMID: 21700483, 22479560). This variant is also known as c.1939G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 92317). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000077955 SCV001338473 pathogenic Adrenoleukodystrophy 2020-04-16 criteria provided, single submitter clinical testing Variant summary: ABCD1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182500 control chromosomes (gnomAD). The variant c.1553G>A (also known as 1939G>A) has been reported in the literature in numerous individuals affected with Adrenoleukodystrophy (e.g. Imamura_1997, Takano_1999, Dvorakova_2001, Guimaraes_2002, Pan_2005, Coll_2005, Wiens_2019), and in several cases the lack of ALD protein in patient derived fibroblasts was demonstrated (e.g. Imamura_1997, Guimaraes_2002, Coll_2005). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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