rs1131691743

Positions:

• chrX-153726027-C-T

Variant summary

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

The NM_000033.4(ABCD1):​c.761C>T​(p.Thr254Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,697 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. 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. T254P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 26)
  • Exomes 𝑓: 0.0000018 (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:7
• Conservation: PhyloP100: 7.55

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain ABC transmembrane type-1 (size 292) in uniprot entity ABCD1_HUMAN there are 43 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153726027-C-T is Pathogenic according to our data. Variant chrX-153726027-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430026.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.761C>T	p.Thr254Met	missense_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.761C>T	p.Thr254Met	missense_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.761C>T	p.Thr254Met	missense_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.761C>T	p.Thr254Met	missense_variant	1/10	1	NM_000033.4	ENSP00000218104	P1
ABCD1	ENST00000370129.4	c.206C>T	p.Thr69Met	missense_variant	1/2	2		ENSP00000359147

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 113919 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 36041 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1089697 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 356927

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: 0.00000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 113919 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 36041

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 25, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 430026). This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 8566952, 23419472; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 254 of the ABCD1 protein (p.Thr254Met). -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	Identified in an adult female with progressive worsening gait, leg stiffness and increased urinary urgency (D Bargiela et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); A different missense change at this residue (T254A) has been reported as likely pathogenic in the published literature and at GeneDx in association with X-linked adrenoleukodystrophy (Turks et al., 2018); 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: 23419472, 8566952, 30902905, 30787906, 24154795, 30069915, 32482842, 33920672) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2017

The p.T254M variant (also known as c.761C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 761. The threonine at codon 254 is replaced by methionine, an amino acid with similar properties. This variant occurred sporadically in one adrenoleukodystrophy/adrenomyeloneuropathy family and one Norwegian X-linked adrenoleukodystrophy family (Krasemann EW et al. Hum. Genet., 1996 Feb;97:194-7; Horn MA et al. Pediatr. Neurol., 2013 Mar;48:212-9). In addition, this variant was identified in a female with adrenomyeloneuropahty (Bargiela D et al. Pract Neurol, 2014 Jun;14:182-4). 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. -

ABCD1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2022

The ABCD1 c.761C>T variant is predicted to result in the amino acid substitution p.Thr254Met. This variant has been reported in hemizygous state in individuals with adrenoleukodystrophy and adrenomyeloneuropathy phenotypes. In at least one report, the variant was documented to occur de novo (Krasemann et al. 1996. PubMed ID: 8566952; Foschi et al. 2019. PubMed ID: 30787906). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.96		Gain of MoRF binding (P = 0.0955);.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.81

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: rs1131691743; hg19: chrX-152991482;