chrX-153726153-A-G

Variant names:

• chrX-153726153-A-G
• rs797044610
• NM_000033.4:c.887A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.887A>G​(p.Tyr296Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000096 in 1,041,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. Y296S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.93
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• X-linked cerebral adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary spastic paraplegia

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• adrenomyeloneuropathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153726152-TA-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 1297042.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153726153-A-G is Pathogenic according to our data. Variant chrX-153726153-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.887A>G	p.Tyr296Cys	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.887A>G	p.Tyr296Cys	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.887A>G	p.Tyr296Cys	missense	Exon 1 of 10	ENSP00000218104.3
	ABCD1	ENST00000370129.4	TSL:2	c.332A>G	p.Tyr111Cys	missense	Exon 1 of 2	ENSP00000359147.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.60e-7 AC: 1 AN: 1041684 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 329496

African (AFR) AF: 0.00 AC: 0 AN: 25085

American (AMR) AF: 0.00 AC: 0 AN: 27658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16840

East Asian (EAS) AF: 0.00 AC: 0 AN: 28169

South Asian (SAS) AF: 0.00 AC: 0 AN: 46128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 813572

Other (OTH) AF: 0.00 AC: 0 AN: 43765

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000427 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:5

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 10, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 296 of the ABCD1 protein (p.Tyr296Cys). 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: 10190819, 11748843, 15800013, 16087056, 16415970, 21068741, 22479560, 25275259, 26454440; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 193033). 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%. For these reasons, this variant has been classified as Pathogenic.

Aug 21, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000193033 /PMID: 10190819 /3billion dataset). Different missense changes at the same codon (p.Tyr296His, p.Tyr296Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000193035, VCV000496882, VCV001297042 /PMID: 35466195). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM5,PP2,PP3. This variant was detected in hemizygous state.

not provided Pathogenic:4

Sep 11, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 34826210, 36438947, 36087940, 16996397, 25275259, 21068741, 11748843, 14767898, 17504626, 26454440, 16415970, 16087056, 15800013, 10190819, 22479560, 34997422, 35645283, 30902905)

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCD1: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate, PP3

Jul 30, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Nov 30, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y296C variant (also known as c.887A>G), located in coding exon 1 of the ABCD1 gene, results from an A to G substitution at nucleotide position 887. The tyrosine at codon 296 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a few individuals with adrenoleukodystrophy (Takano H et al. Arch. Neurol., 1999 Mar;56:295-300; Kemp S et al. Hum. Mutat., 2001 Dec;18:499-515; Pan H et al. Pediatr. Neurol., 2005 Aug;33:114-20; Asheuer M et al. Hum. Mol. Genet., 2005 May;14:1293-303; Sutovský S et al. Neuro Endocrinol. Lett., 2014;35:411-6; Chu SS et al. World J Pediatr, 2015 Nov;11:366-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		8.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Gain of sheet (P = 0.0011)
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044610; hg19: chrX-152991608;