The variant c.649A>G (p.Lys217Glu) (NM_000033.4) is a missense variant in exon 1. At least one patient with this variant displayed Addison's disease/adrenal insufficiency, with positive family history (similarly affected sibling), and elevated VLCFAs. These symptoms are highly specific for adrenoleukodystrophy (PP4_Moderate, PMID: 11438993). This variant has been reported in at least 2 other probands meeting PP4_Supporting phenotype criteria (PS4_moderate; PMID: 11748843, 21300044). The ALD database (https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1) currently reports a total of 7 patients. The variant has been reported to segregate with adrenoleukodystrophy in ≥2 affected meioses from 1 family (PP1; PMID: 11438993). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen Peroxisomal Disorders VCEP threshold of ≥0.85, evidence that correlates with impact to ABCD1 function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). Beta-oxidation assay in ALD patient fibroblasts transfected with the variant showed activity ≤26% of WT, indicating that this variant impacts protein function (PMID: 11438993)(PS3_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal VCEP: PP4_Moderate, PS4_moderate, PP1, PP3, PM2_supporting, PS3_supporting. (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0)