NM_000033.4:c.1825G>A

Variant names:

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

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]

ABCD1 links:

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

PLXNB3-AS1 links:

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
ABCD1	NM_000033.4 link	c.1825G>A	p.Glu609Lys	missense_variant	Exon 8 of 10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 link	c.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
ABCD1	ENST00000218104.6 link	c.1825G>A	p.Glu609Lys	missense_variant	Exon 8 of 10	1	NM_000033.4	ENSP00000218104.3		P33897
PLXNB3-AS1	ENST00000434284.1 link	n.72-4453C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1086846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:6

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. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

- -

Aug 20, 2023

Baylor Genetics

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

- -

Sep 01, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

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

- -

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. -

May 01, 2014

Eurofins Ntd Llc (ga)

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

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.95

Sift

Uncertain

0.022

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.96

MVP

1.0

MPC

1.6

ClinPred

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over