rs128624219

Positions:

• chrX-153736232-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000218104.6(ABCD1):​c.1202G>A​(p.Arg401Gln) 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. R401W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 ENST00000218104.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.37

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]

LOC124905226 (HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in ENST00000218104.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153736231-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 488393.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-153736232-G-A is Pathogenic according to our data. Variant chrX-153736232-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1202G>A	p.Arg401Gln	missense_variant	3/10	ENST00000218104.6	NP_000024.2
LOC124905226	XR_007068350.1	n.4119C>T		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1	c.1202G>A	p.Arg401Gln	missense_variant	3/11		XP_047297872.1
ABCD1	XM_047441917.1	c.1202G>A	p.Arg401Gln	missense_variant	3/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1202G>A	p.Arg401Gln	missense_variant	3/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.581-273C>T		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.205G>A		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R401Q in ABCD1 (NM_000033.4) causes the same amino acid change as a previously established pathogenic variant. The p.R401Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.R401Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 401 of ABCD1 is conserved in all mammalian species. The nucleotide c.1202 in ABCD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 401 of the ABCD1 protein (p.Arg401Gln). 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: 8566952, 15811009, 21966424, 23419472, 26388597). In at least one individual the variant was observed to be de novo. This variant is also known as G1588A. ClinVar contains an entry for this variant (Variation ID: 11300). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg401 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 10190819, 22479560), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 17, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); 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: 36801247, 36380532, 10551832, 26388597, 7849723, 10980539, 8566952, 33920672, 34826210, 34649108, 10737980, 11336405, 20800589, 21889498, 21068741, 33794216, 21966424, 22280810, 30902905, 26454440, 12402273, 15811009, 23419472, 33247909, 34291142, 7668254, 21300044, 35676282) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 21, 2018

The ABCD1 c.1202G>A; p.Arg401Gln variant (rs128624219) has been described in several individuals and families affected with X-linked adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN; see link to ALD ABCD1 database and references therein, Kemp 2001, Krasemann 1996, Kumar 2011, Shimozawa 2011, Watkins 1995). It contains an entry in ClinVar (Variation ID: 11300), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 401 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, other variants at this codon (c.1201C>T; p.Arg401Trp and c.1201C>G; p.Arg401Gly) have been described in several individuals with ALD and are considered pathogenic (see link to ALD ABCD1 database and references therein, Shimozawa 2011). Based on available information, this variant is considered pathogenic. References: ALD ABCD1 database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Kemp S et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001 Dec;18(6):499-515. Krasemann E et al. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996 Feb;97(2):194-7. Kumar N et al. Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India. PLoS One. 2011;6(9):e25094. Shimozawa N et al. X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan. J Hum Genet. 2011 Feb;56(2):106-9. Watkins P et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995 Aug;57(2):292-301. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.91		Loss of phosphorylation at S404 (P = 0.0539);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
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

Other links and lift over

dbSNP: rs128624219; hg19: chrX-153001686; COSMIC: COSV54386939;