rs201568579

Positions:

• chrX-153740600-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1661G>A​(p.Arg554His) 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: 25)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.78

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 (HGNC:):

ACMG classification

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, 0.954
• PP5: Variant X-153740600-G-A is Pathogenic according to our data. Variant chrX-153740600-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 166625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153740600-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1661G>A	p.Arg554His	missense_variant	7/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.1961G>A	p.Arg654His	missense_variant	8/11		XP_047297872.1
ABCD1	XM_047441917.1	c.1717G>A	p.Val573Met	missense_variant	8/8		XP_047297873.1
LOC124905226	XR_007068350.1	n.948C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1661G>A	p.Arg554His	missense_variant	7/10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000443684.2	n.664G>A		non_coding_transcript_exon_variant	6/6	3
PLXNB3-AS1	ENST00000434284.1	n.72-2022C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 554 of the ABCD1 protein (p.Arg554His). This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 9242200, 10227685, 23664929, 24719134, 26260157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166625). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This sequence change replaces arginine with histidine at codon 554 of the ABCD1 protein (p.Arg554His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been observed in unrelated individuals and to segregate with adrenoleukodystrophy in a family (Jiang MY et al, Park HJ et al, Zhan ZX et al). The amino acid Arg at position 554 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg554His in ABCD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Arg554His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant is not present in population databases (ExAC no frequency).For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 15800013, 17504626, 16087056, 9242200, 10227685, 28919002, 26260157, 10737980, 11748843, 14767898, 21068741, 21476988, 22176151, 16415970, 30902905, 23664929, 15811009, 15643618, 23566833, 20859061, 34069712, 31405945, 24719134, 22479560, 32003821) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2022	- -

ABCD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The ABCD1 c.1661G>A variant is predicted to result in the amino acid substitution p.Arg554His. This variant has been reported frequently as causative for X-linked adrenoleukodystrophy (see for example Zhan et al. 2013. PubMed ID: 23664929; Lachtermacher et al. 2000. PubMed ID: 10737980). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.0028	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.98
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

Other links and lift over

dbSNP: rs201568579; hg19: chrX-153006054;