X-153726104-C-T

Variant names:

Variant summary

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

The NM_000033.4(ABCD1):c.838C>T(p.Arg280Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,067,632 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 (★★).

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.46

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:

Genome browser will be placed here

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, 0.962

PP5

Variant X-153726104-C-T is Pathogenic according to our data. Variant chrX-153726104-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35643.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.838C>T	p.Arg280Cys	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 1 of 11		XP_047297872.1
ABCD1	XM_047441917.1 link	c.838C>T	p.Arg280Cys	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.838C>T	p.Arg280Cys	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3		P33897
ABCD1	ENST00000370129.4 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 1 of 2	2		ENSP00000359147.3		A6NEP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000155

AC:

AN:

128935

Hom.:

AF XY:

0.00

AC XY:

AN XY:

33885

show subpopulations

Gnomad AFR exome

AF:

0.000107

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000939

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000187

AC:

AN:

1067632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000346

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000842

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:6

May 08, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 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 cysteine, which is neutral and slightly polar, at codon 280 of the ABCD1 protein (p.Arg280Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 11748843, 15811009; https//adrenoleukodystrophy.info/mutations-and-variants-in-abcd1, internal data). ClinVar contains an entry for this variant (Variation ID: 35643). 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%. This variant disrupts the p.Arg280 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 11798073), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Aug 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29443243, 11748843, 33920672, 35466195, 35076462, 36076658, 15811009) -

Jun 18, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCD1 c.838C>T; p.Arg280Cys variant (rs193922098) is reported in several individuals with X-linked adrenoleukodystrophy and increased very-long-chain fatty acids (see link to ABCD1 variant database, Coll 2005, Isaacs 2014). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 35643) and is reported in the general population in 2 out of 128,935 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 280 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Link to ABCD1 database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Coll MJ et al. X-linked Adrenoleukodystrophy in Spain. Identification of 26 Novel Mutations in the ABCD1 Gene in 80 Patients. Improvement of Genetic Counseling in 162 Relative Females. Clin Genet. 2005 May;67(5):418-24. Isaacs D et al. Adult-onset Adrenoleukodystrophy Presenting After Chemotherapy: No Black and White Matter. Neurol Clin Pract. 2014 Apr;4(2):168-170. -

Apr 25, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

History of neurodevelopmental disorder

Pathogenic:1

Jun 05, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCD1-related disorder

Pathogenic:1

Jun 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCD1 c.838C>T variant is predicted to result in the amino acid substitution p.Arg280Cys. This variant has been reported in multiple unrelated individuals with adrenoleukodystrophy (Kemp et al. 2001. PubMed ID: 11748843; Coll et al. 2005. PubMed ID: 15811009; Isaacs et al. 2014. PubMed ID: 29443243). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-152991559-C-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.5

H;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.88

MVP

1.0

MPC

1.8

ClinPred

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

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