rs1557054873

chrX-153740711-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):c.1772G>A(p.Arg591Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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]

LOC124905226 (HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000033.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153740710-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-153740711-G-A is Pathogenic according to our data. Variant chrX-153740711-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1772G>A	p.Arg591Gln	missense_variant	7/10	ENST00000218104.6
LOC124905226	XR_007068350.1	n.837C>T		non_coding_transcript_exon_variant	1/2
ABCD1	XM_047441916.1	c.2072G>A	p.Arg691Gln	missense_variant	8/11
ABCD1	XM_047441917.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1772G>A	p.Arg591Gln	missense_variant	7/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-2133C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1096262 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362870

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 591 of the ABCD1 protein (p.Arg591Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked cerebellar adrenoleukodystrophy and adrenomyeloneuropathy (PMID: 7581394, 7668254, 19129531, 22280810, 23566833). ClinVar contains an entry for this variant (Variation ID: 458635). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 9425230). 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	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jul 05, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 19, 2023	Criteria applied: PS4,PM1,PM5,PM2_SUP,PP3 -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Published functional studies demonstrate that R591Q disrupts activity but not expression of ALDP (Braiterman et al., 1998); 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: 7668254, 19129531, 17372139, 7581394, 23566833, 35466195, 32003821, 22280810, 33920672, 9425230) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The c.1772G>A (p.R591Q) alteration is located in exon 7 (coding exon 7) of the ABCD1 gene. This alteration results from a G to A substitution at nucleotide position 1772, causing the arginine (R) at amino acid position 591 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in several individuals with X-linked adrenoleukodystrophy (ALD), including individuals with adrenomyeloneuropathy and adult cerebral ALD (Watkins, 1995; Costello, 2009; Niu, 2013; Lee, 2020). It was also identified in two symptomatic females with skewed X-inactivation (Jung, 2007; Salsano, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.92		Gain of helix (P = 0.132);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.92

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: rs1557054873; hg19: chrX-153006165;