ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1166G>A (p.Arg389His) (rs886044777)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000268436 SCV000612225 likely pathogenic not provided 2019-06-05 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically enriched in patients compared to ethnically matched controls. Results on protein functions were inconclusive.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000268436 SCV000700868 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing
Invitae RCV000984141 SCV001198016 pathogenic Adrenoleukodystrophy 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 389 of the ABCD1 protein (p.Arg389His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with ABCD1-related disease (PMID: 7825602, 15811009, 7581394, 24719134). ClinVar contains an entry for this variant (Variation ID: 281336). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22479560, 15811009, 8566952, 7825602). 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.
Integrated Genetics/Laboratory Corporation of America RCV000984141 SCV001361104 likely pathogenic Adrenoleukodystrophy 2019-10-02 criteria provided, single submitter clinical testing Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183351 control chromosomes (gnomAD). c.1166G>A has been reported in the literature associated with Addison Disease or Adrenomyeloneuropathy (AMN) phenotypes (e.g. Coll_2005, Kok_1995). These data indicate that the variant is likely to be associated with disease. In functional studies compared to controls, the variant showed less than 50% of peroxisomal beta-oxidation activity and approximately 40% of ALDP protein levels (Schackmann_2016, Zhang_2011). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000984141 SCV001132113 likely pathogenic Adrenoleukodystrophy 2017-05-09 no assertion criteria provided clinical testing

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