NM_000033.4:c.1825G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000033.4(ABCD1):​c.1825G>A​(p.Glu609Lys) 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

ABCD1
NM_000033.4 missense

Scores

11
5
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 10.0
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant X-153743031-G-A is Pathogenic according to our data. Variant chrX-153743031-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 166626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153743031-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCD1NM_000033.4 linkc.1825G>A p.Glu609Lys missense_variant Exon 8 of 10 ENST00000218104.6 NP_000024.2 P33897
ABCD1XM_047441916.1 linkc.2125G>A p.Glu709Lys missense_variant Exon 9 of 11 XP_047297872.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCD1ENST00000218104.6 linkc.1825G>A p.Glu609Lys missense_variant Exon 8 of 10 1 NM_000033.4 ENSP00000218104.3 P33897
PLXNB3-AS1ENST00000434284.1 linkn.72-4453C>T intron_variant Intron 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1086846
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
355818
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:6
Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Sep 01, 2020
Johns Hopkins Genomics, Johns Hopkins University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 20, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2023
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 609 of the ABCD1 protein (p.Glu609Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN), and adult cerebral adrenoleukodystrophy (PMID: 7825602, 11748843, 20661612, 21966424). ClinVar contains an entry for this variant (Variation ID: 166626). 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%. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 21476988). This variant disrupts the p.Glu609 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 21476988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4
May 01, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 30, 2021
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging. -

Jul 19, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27766264, 21966424, 20661612, 23891399, 21476988, 11748843, 15800013, 21068741, 24480483, 8892025, 19892975, 7825602, 15811009, 8566952, 30902905, 32954314) -

Apr 14, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ABCD1-related disorder Pathogenic:1
Jun 03, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ABCD1 c.1825G>A variant is predicted to result in the amino acid substitution p.Glu609Lys. This variant has been reported in multiple individuals with X-linked adrenoleukodystrophy (see for example, Table 2, Ligtenberg et al. 1995. PubMed ID: 7825602; Cartier et al. 2009. PubMed ID: 19892975; Table 3, Kumar et al. 2011. PubMed ID: 21966424). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies using patient fibroblasts suggest this variant results in the absence of protein (Table 4, Kemp et al. 2001. PubMed ID: 11748843; Table 1, Zhang et al. 2011. PubMed ID: 21476988). An alternate missense variant affecting the same amino acid (p.Glu609Gly) has been reported in multiple individuals with X-linked adrenoleukodystrophy (Table 2, Ligtenberg et al. 1995. PubMed ID: 7825602; Zhu et al. 2023. PubMed ID: 37845577). Given this evidence, the c.1825G>A (p.Glu609Lys) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.70
D
BayesDel_noAF
Pathogenic
0.77
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.022
D
Sift4G
Uncertain
0.024
D
Polyphen
1.0
D
Vest4
0.96
MVP
1.0
MPC
1.6
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.83
gMVP
1.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150346282; hg19: chrX-153008485; API