NM_000033.4:c.1979G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000033.4(ABCD1):​c.1979G>T​(p.Arg660Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R660P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

ABCD1
NM_000033.4 missense

Scores

15
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.92
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)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-153743334-G-T is Pathogenic according to our data. Variant chrX-153743334-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 458637.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCD1NM_000033.4 linkc.1979G>T p.Arg660Leu missense_variant Exon 9 of 10 ENST00000218104.6 NP_000024.2 P33897
ABCD1XM_047441916.1 linkc.2279G>T p.Arg760Leu missense_variant Exon 10 of 11 XP_047297872.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCD1ENST00000218104.6 linkc.1979G>T p.Arg660Leu missense_variant Exon 9 of 10 1 NM_000033.4 ENSP00000218104.3 P33897
PLXNB3-AS1ENST00000434284.1 linkn.72-4756C>A intron_variant Intron 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1
Sep 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 660 of the ABCD1 protein (p.Arg660Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked adrenoleukodystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 458637). This variant disrupts the p.Arg660 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 11438993, 21889498, 21966424; Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.80
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.9
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.90
Loss of helix (P = 0.0444);
MVP
1.0
MPC
1.7
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.84
gMVP
0.97

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: rs1557055340; hg19: chrX-153008788; API