Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000033.4(ABCD1):c.-16_10del (p.Met1fs)

CA278121

11317 (ClinVar)

Gene: ABCD1 (HGNC:215)
Condition: adrenoleukodystrophy (MONDO:0018544)
Inheritance Mode: X-linked inheritance
UUID: bdb7d73c-de9f-48d0-8d4c-42d9dc330c14
Approved on: 2026-04-15
Published on: 2026-04-15

HGVS expressions

NM_000033.4(ABCD1):c.-16_10del (p.Met1fs)
NM_000033.4:c.-16_10del
NC_000023.11:g.153725251_153725276del
CM000685.2:g.153725251_153725276del
NC_000023.10:g.152990706_152990731del
CM000685.1:g.152990706_152990731del
NC_000023.9:g.152643900_152643925del
NG_009022.2:g.5384_5409del
NG_023231.1:g.4473_4498del
ENST00000218104.6:c.-16_10del
ENST00000218104.5:c.-16_10del
NM_000033.3:c.-16_10del
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PP4_Moderate PVS1_Moderate PP1_Strong
Not Met criteria codes 22
BA1 PP3 PP2 PM4 PM5 PM3 PM1 PM6 BS2 BS4 BS3 BS1 PS1 PS2 PS4 PS3 BP3 BP2 BP4 BP1 BP5 BP7

Evidence Links 0

Expert Panel

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 c.-16_10del (NM_000033.4) variant in ABCD1 is a variant occurring in the 5' UTR. This variant is absent from gnomAD v2.1.1 & v3.1.2 (PM2_Supporting). This variant may cause a truncated or nonfunctional protein by altering the start codon of the coding sequence. The next in-frame methionine is located at codon 67. Disruption of the initiator codon has been observed in individual(s) with adrenomyeloneuropathy (PVS1_Moderate; PMID: 11739809, 18306728). The variant has been reported to segregate with adrenoleukodystrophy in 12 affected (genotype and phenotype positive) family members (total 52 individuals). There are 7 affected segregations (including the proband) (PP1_Strong; PMID:11739809). At least one male patient with this variant displayed adrenomyeloneuropathy, a family history with X-linked inheritance, ABCD1 gene sequencing, and VLCFA levels in fibroblasts that were significantly higher than those from normal controls (PP4_Moderate; PMID: 11739809). In summary, this variant meets the criteria to be classified as likely pathogenic for ABCD1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal Disorders Variant Curation Expert Panel: PVS1_moderate, PM2_supporting, PP1_strong, PP4_Moderate. (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1, with good coverage (PM2_Supporting).
PP4_Moderate
Utilizing the ABCD1 Phenotype Specification Table created by the ClinGen Peroxisomal Disorders VCEP, at least one male patient with this variant displayed adrenomyeloneuropathy, a family history with X-linked inheritance (and at least one affected family member was a male), ABCD1 gene sequencing, and VLCFA levels in fibroblasts that were significantly higher than those from normal controls (C26/C22 ratio 0.92 versus 0.04, respectively). Exclusion of the 4 pseudogenes (on chromosomes 2, 10, 16 & 22) is assumed to be confirmed (Information on ABCD1 pseudogenes has been available since 1997, PMID: 9215666, 35053399). (PP4_Moderate); PMID: 11739809
PVS1_Moderate
The c.-16_10del (p. Met1fs) variant in ABCD1 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. This sequence change affects the initiator methionine of the ABCD1 mRNA. The next in-frame methionine is located at codon 67. Disruption of the initiator codon has been observed in individual(s) with adrenomyeloneuropathy (PVS1_Moderate; PMID: 11739809, 18306728).
PP1_Strong
The variant has been reported to segregate with adrenoleukodystrophy in 12 affected (genotype and phenotype positive) family members (total 52 individuals). There are 7 affected segregations (including the proband); PMID:11739809
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Proband form PMID: 18306728 carries a different initiation codon than the current variant and cannot be counted towards PS4.
PS3
VLCFA beta-oxidation assays in affected hemizygote fibroblasts showed that VLCFA beta-oxidation is reduced to 20% of normal, indicating that this variant impacts protein function (PMID: 11739809)
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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