chrX-153740711-G-C

Variant names:

• chrX-153740711-G-C
• rs1557054873
• NM_000033.4:c.1772G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):​c.1772G>C​(p.Arg591Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.78
• Publications: 0 publications found

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153740711-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 458635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153740711-G-C is Pathogenic according to our data. Variant chrX-153740711-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2737418.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.1772G>C	p.Arg591Pro	missense	Exon 7 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2072G>C	p.Arg691Pro	missense	Exon 8 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-2133C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1772G>C	p.Arg591Pro	missense	Exon 7 of 10	ENSP00000218104.3
	PLXNB3-AS1	ENST00000434284.1	TSL:3	n.72-2133C>G		intron	N/A
	ABCD1	ENST00000443684.2	TSL:3	n.*107G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Jul 15, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCD1 c.1772G>C (p.Arg591Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 182606 control chromosomes. c.1772G>C has been observed in individuals affected with Adrenoleukodystrophy (e.g. Horn_2013, Kemp_2001). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as likely pathogenic/pathogenic by our lab (c.1772G>A, p.Arg591Gln), supporting the critical relevance of codon 591 to ABCD1 protein function. One publication reports absent ABCD1 protein product in a Adrenoleukodystrophy patient (e.g. Kemp_2001). The following publications have been ascertained in the context of this evaluation (PMID: 23419472, 11748843). ClinVar contains an entry for this variant (Variation ID: 2737418). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 591 of the ABCD1 protein (p.Arg591Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 23419472). ClinVar contains an entry for this variant (Variation ID: 2737418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg591 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7668254, 10190819, 12175782, 19129531, 22280810, 23566833, 24154795, 28503596). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.95		Gain of catalytic residue at Q590 (P = 0.134)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.99
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557054873; hg19: chrX-153006165;