NM_000033.4:c.1552C>T

Variant names:

• chrX-153740155-C-T
• rs128624224
• NM_000033.4:c.1552C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1552C>T​(p.Arg518Trp) 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: 25)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.985

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]

LOC124905226 (HGNC:):

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

ACMG classification

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, 0.995
• PP5: Variant X-153740155-C-T is Pathogenic according to our data. Variant chrX-153740155-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153740155-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1552C>T	p.Arg518Trp	missense_variant	Exon 6 of 10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.1852C>T	p.Arg618Trp	missense_variant	Exon 7 of 11		XP_047297872.1
ABCD1	XM_047441917.1	c.1608C>T	p.Ser536Ser	synonymous_variant	Exon 7 of 8		XP_047297873.1
LOC124905226	XR_007068350.1	n.1393G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1552C>T	p.Arg518Trp	missense_variant	Exon 6 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000443684.2	n.555C>T		non_coding_transcript_exon_variant	Exon 5 of 6	3
PLXNB3-AS1	ENST00000434284.1	n.72-1577G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:6

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PM5+PP3_Moderate+PP4 -

Aug 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCD1 c.1552C>T (p.Arg518Trp) results in a non-conservative amino acid change located in the AAA+ ATPase domain 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 177823 control chromosomes (gnomAD and publication). c.1552C>T has been reported in the literature in multiple individuals affected with Adrenoleukodystrophy including symptomatic female carriers (Chu_2015, Fanen_1994, Feigenbaum_1996, Guettsches_2010, Guimaraes_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg518 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10190819, 12175782, 15811009, 16087056, 21068741, 23419472, 23566833, 26260157). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 11307). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 8651290, 12175782, 20661612, 26454440). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 518 of the ABCD1 protein (p.Arg518Trp). -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCD1 NM_000033.3 exon 6 p.Arg518Trp (c.1552C>T): This variant has been reported in the literature in at least 3 individuals with a clinical diagnosis or features of adrenoleukodystrophy (ALD), segregating with disease in at least 1 affected family member (Fanen 1994 PMID:8040304, Guettsches 2010 PMID:20195870, Shimozawa 2011 PMID:21068741). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:11307). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this same codon (p.Arg518Pro, p.Arg518Gly, p.Arg518Gln) have been reported in the literature, suggesting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

not provided Pathogenic:2

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked spondyloepimetaphyseal dysplasia Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCD1 p.Arg518Trp variant was identified in 5 of 318 proband chromosomes (frequency: 0.02) from individuals or families with X-linked adrenoleukodystrophy, and was not identified in 200 control chromosomes from healthy individuals (Chu 2015, Fanen 1994, Matsukawa 2010, Feigenbaum 1996). The variant was also found in case study by Guettsches (2010) in two symptomatic adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) female carriers. The son of one of the carriers died of ALD at age of 9. The variant was identified in dSNP (rs128624224) as "With Pathogenic allele", ClinVar (classified as pathogenic by OMIM and EGL genetic Diagnistics), the ALD Mutation Database (as pathogenic, identified in 19 ALD patients; no detectable ALDP in patient cells) and LOVD (as likely pathogenic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The protein analysis study by Feigenbaum (1996) identifies the variant resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. The p.Arg518 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.91
MutPred		0.97		Gain of catalytic residue at L516 (P = 0.0119);
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.95

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: rs128624224; hg19: chrX-153005609;