rs782041940

Positions:

• chrX-153743255-G-A
• chrX-153743255-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000033.4(ABCD1):​c.1900G>A​(p.Ala634Thr) 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).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8
• Conservation: PhyloP100: 10.0

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain ABC transporter (size 226) in uniprot entity ABCD1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1900G>A	p.Ala634Thr	missense_variant	9/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.2200G>A	p.Ala734Thr	missense_variant	10/11		XP_047297872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1900G>A	p.Ala634Thr	missense_variant	9/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4677C>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: 9.14e-7 AC: 1 AN: 1094646 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1 AN XY: 361268

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 28, 2019	This ABCD1 variant is absent from large population datasets and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classifies it as likely pathogenic and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this variant may create a potential cryptic splice site, however, its effect on splicing has not been studied experimentally to our knowledge. The clinical significance of c.1900G>A is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 20, 2022	Criteria applied: PS4_MOD, PM2_SUP, PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 634 of the ABCD1 protein (p.Ala634Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy (PMID: 35076462; external communication). ClinVar contains an entry for this variant (Variation ID: 282253). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2024	Classified as a variant of uncertain significance in individuals with a positive newborn screen for X-ALD (PMID: 33920672, 35076462); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34946879, 33920672, 35076462, 34506099) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 24, 2023	- -

ABCD1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2023

The ABCD1 c.1900G>A variant is predicted to result in the amino acid substitution p.Ala634Thr. This variant was reported in individuals with borderline adrenoleukodystrophy, but was classified as a variant of uncertain significance (Burton et al. 2022. PubMed ID: 35076462; Supplemental table, Matteson et al. 2021. PubMed ID: 33920672; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). Functional studies in fibroblasts suggest this variant impacts ABCD1 activity (van de Stadt et al. 2021. PubMed ID: 34946879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While we suspect that this variant could be pathogenic, at this time we interpret its clinical significance as uncertain due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of glycosylation at A634 (P = 0.0908);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs782041940; hg19: chrX-153008709;