dbSNP rs1131691916: ABCD1:p.Arg189Trp (chrX-153725831-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000033.4(ABCD1):c.565C>T(p.Arg189Trp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 26)

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.22

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant X-153725831-C-T is Pathogenic according to our data. Variant chrX-153725831-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4 link	c.565C>T	p.Arg189Trp	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 link	c.565C>T	p.Arg189Trp	missense_variant	Exon 1 of 11		XP_047297872.1
ABCD1	XM_047441917.1 link	c.565C>T	p.Arg189Trp	missense_variant	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.565C>T	p.Arg189Trp	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3		P33897
ABCD1	ENST00000370129.4 link	c.10C>T	p.Arg4Trp	missense_variant	Exon 1 of 2	2		ENSP00000359147.3		A6NEP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:6

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the ABCD1 protein (p.Arg189Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ABCD1-related conditions (PMID: 10737980, 15811009, 30069915). ClinVar contains an entry for this variant (Variation ID: 430349). 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. -

Mar 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430349, PMID:10737980, PS1_S). A different missense change at the same codon has been reported to be associated with ABCD1 related disorder (PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, 3CNET: 0.986, PP3_P). A missense variant is a common mechanism associated with Adrenomyeloneuropathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 27, 2021

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria Codes: PS4_Mod PM2 PP3 PP4 -

not provided

Pathogenic:3

Jun 27, 2024

GeneDx

Significance: Likely 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: 30069915, 15811009, 31589614, 10737980, 33920672, 35466195, 34649108, 36046390) -

May 29, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Apr 17, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R189W variant (also known as c.565C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 565. The arginine at codon 189 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in one individual with Addison disease and one individual with adrenomyeloneuropathy; both individuals had elevated very long chain fatty acid plasma concentrations (Lachtermacher MB et al. Hum. Mutat., 2000;15:348-53; Coll MJ et al. Clin. Genet., 2005 May;67:418-24). 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.74

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.90

MutPred

0.93

Loss of disorder (P = 0.0082);.;

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.5

Varity_R

0.95

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over