ABCD1 p.Ser606Pro

The NM_000033.4:c.1816T>C variant in ABCD1 is a missense variant predicted to cause substitution of serine by proline at amino acid 606 (p.Ser606Pro). This variant has been reported in 6 probands meeting ABCD1 phenotype criteria at the supporting strength (PP4, PS4; PMIDs: 21700483), with one of them reported to be de novo (PM6_Supporting, PMID: 21700483, 22479560, 21966424, 21889498, 8651290). The variant is absent from gnomAD v4.1 (PM2_Supporting). β-oxidation activity assay in ALD fibroblasts showed <50% of that of WT, although a substantial amount of mutant ALDP was expressed in the cells, indicating that this variant impacts protein function (PS3_Supporting, PMID: 17542813). This missense variant has a REVEL score of 0.877, which is above the PP3 threshold (>=0.85) for ABCD1 set by the Peroxisomal VCEP. Another missense variant (c.1817C>T, p.Ser606Leu, ClinVar ID: 11310) in the same codon has been classified as pathogenic for X-linked adrenoleukodystrophy by the ClinGen Peroxisomal VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal VCEP: PS4, PM2_Supporting, PM5, PP4, PM6_Supporting, PP3, PS3_Supporting. (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0).