rs1131691954

Positions:

• chrX-153726146-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000033.4(ABCD1):​c.880G>A​(p.Ala294Thr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A294V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.59

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153726146-G-A is Pathogenic according to our data. Variant chrX-153726146-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430421.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.880G>A	p.Ala294Thr	missense_variant	1/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.880G>A	p.Ala294Thr	missense_variant	1/11
ABCD1	XM_047441917.1	c.880G>A	p.Ala294Thr	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.880G>A	p.Ala294Thr	missense_variant	1/10	1	NM_000033.4	P1
ABCD1	ENST00000370129.4	c.325G>A	p.Ala109Thr	missense_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1046048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 331318

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:4

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	Oct 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 294 of the ABCD1 protein (p.Ala294Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 8651290; Invitae). ClinVar contains an entry for this variant (Variation ID: 430421). 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. This variant disrupts the p.Ala294 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 16018167), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5. This variant was detected in hemizygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2024	Variant summary: ABCD1 c.880G>A (p.Ala294Thr) results in a non-conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 112142 control chromosomes (gnomAD). c.880G>A has been reported in the literature in hemizygous individuals affected with Adrenoleukodystrophy (e.g. Feigenbaum_1996, and in the ALD info database), and was also found in newborn screenings in heterozygous female infants with biochemical features of decreased ABCD1 function (e.g. Matteson_2021, Priestley_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, missense variants affecting the same amino acid (p.A294V), and nearby amino acid residues are reported in affected individuals (e.g.: p.E291D/G/K, p.E292D/K, p.Y296C/H/S, p.G298R/D/S/V; see HGMD), suggesting that this protein region is functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 10190819, 8651290, 35466195, 33920672). ClinVar contains an entry for this variant (Variation ID: 430421). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	Reported in an individual with adrenomyeloneuropathy, no additional clinical information provided (PMID: 8651290); Not observed 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: 35466195, 35479665, 8651290) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.98		Gain of glycosylation at A294 (P = 0.0591);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131691954; hg19: chrX-152991601;