The c.521A>G variant in ABCD1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 174 (p.Tyr174Cys).At least one patient with this variant displayed rapid progression of inflammatory white matter demyelination in adolescence, had a X-linked pattern family history of disease including an affected male, and abnormal very long chain fatty acid testing, which is highly specific for adrenoleukodystrophy (PP4_Moderate, PMID:24722136). This variant has been reported in six more probands meeting a family history with an X-linked inheritance pattern where at least one family member is male or rapid progression of inflammatory white matter demyelination in childhood, and abnormal very long chain fatty acid testing (PS4; PMID:11336405, 28895702, 21068741, 26260157, 24722136). This variant has been assumed as a de novo occurrence with unconfirmed parental relationships in one individual with X-linked adrenoleukodystrophy (PM6_Supporting; PMID:11336405). The variant has been reported to segregate with X-linked adrenoleukodystrophy in eight affected family members from one family (PP1_Strong; PMID:11336405). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1.0 (PM2_Supporting). Beta-oxidation assay in X-ALD fibroblasts (163T) showed that the beta-oxidation activity of the variant protein is approximately 5% of wild type ABCD1, indicating that this variant has an impact protein function (PMID:17542813)(PS3_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.85, evidence that correlates with impact to ABCD1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for X-linked adrenoleukodystrophy based on ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal Disorders VCEP: PP1_Strong, PS4, PP3, PP4_Moderate, PM2_Supporting, PM6_Supporting, PS3_Supporting (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0)