Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000033.4:c.284C>A

CA415098539

Gene: ABCD1 (HGNC:215)

Condition: adrenoleukodystrophy (MONDO:0018544)

Inheritance Mode: X-linked inheritance

UUID: 33aebe52-2cab-4078-98b3-0b2d71af13ee

Approved on: 2026-04-16

Published on: 2026-04-16

HGVS expressions

NM_000033.4:c.284C>A

NC_000023.11:g.153725550C>A

CM000685.2:g.153725550C>A

NC_000023.10:g.152991005C>A

CM000685.1:g.152991005C>A

NC_000023.9:g.152644199C>A

NG_009022.2:g.5683C>A

NG_023231.1:g.4197G>T

ENST00000218104.6:c.284C>A

ENST00000218104.5:c.284C>A

NM_000033.3:c.284C>A

Likely Pathogenic

PS4_Supporting PP1_Moderate PM2_Supporting PS3_Supporting PP4

BP4 PP3

Evidence Links 0

Expert Panel

Peroxisomal Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Peroxisomal Disorders VCEP

The NM_000033.4:c.284C>A variant in ABCD1 is a missense variant predicted to cause the substitution of alanine by asparagine at amino acid 95 (p.Ala95Asp). At least one patient with this variant was diagnosed with childhood cerebral form adrenoleukodystrophy (C) and elevated VLCFAs, which are specific for adrenoleukodystrophy (PP4, PMID 23651979). This variant has been reported in 1 additional family meeting PP4 phenotype criteria (PS4_Supporting; PMID 23430809). The variant has been reported to segregate with ABCD1 deficiency in 2 affected meioses in addition to the proband (the proband's sister and nephew) in one family (PP1_Moderate; PMID 23430809). This variant is absent from gnomAD v4.1 (PM2_Supporting). Beta-oxidation activity assays in CADDS fibroblasts lacking the ABCD1 gene were completed. They were transfected with the ABCD1 c.284C>A variant, resulting in scarce expression. The C24:0 Beta-oxidation activities were not recovered, indicating that this variant impacts protein function (PMID: 23430809)(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 Disorders VCEP: PP4, PS4_Supporting, PP1_Moderate, PM2_Supporting, PS3_Supporting (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0)

PS4_Supporting

This variant has been reported in 1 additional family meeting PP4 phenotype criteria (PS4_Supporting; PMID 23430809).

PP1_Moderate

The variant has been reported to segregate with ABCD1 deficiency in 2 affected meioses in addition to the proband (the proband's sister and nephew) in one family (PP1_Moderate; PMID 23430809).

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PS3_Supporting

Beta-oxidation activity assays in CADDS fibroblasts lacking the ABCD1 gene were completed. They were transfected with the ABCD1 c.284C>A variant, resulting in scarce expression. The C24:0 Beta-oxidation activities were not recovered, indicating that this variant impacts protein function (PMID: 23430809)(PS3_Supporting).

PP4

At least one patient with this variant was diagnosed with childhood cerebral form adrenoleukodystrophy (C) and elevated VLCFAs, which are specific for adrenoleukodystrophy (PP4, PMID 23651979).

BP4

The results from 2 in silico predictors (REVEL and SpliceAI) do not agree, providing no evidence that correlates with a damaging or benign impact on ABCD1 function. SpliceAI gives a score of 0.03 for donor gain and 0.00 for acceptor loss, donor loss, and acceptor gain, which are below the threshold of ≤0.2, suggesting that the variant has no impact on splicing. However, REVEL gives a score of 0.81, which is neither above (≥0.85) nor below (≤0.5) the thresholds set predicting a damaging or benign impact on ABCD1 function.

PP3

The computational predictor REVEL gives a score of 0.81, which is neither above (≥0.85) nor below (≤0.5) the thresholds set by the Peroxisomal Disorders VCEP predicting a damaging or benign impact on ABCD1 function.

Curation History

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