rs1057517954

Positions:

• chrX-153725754-G-A
• chrX-153725754-G-C
• chrX-153725754-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.488G>A​(p.Arg163His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.54

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-153725754-G-A is Pathogenic according to our data. Variant chrX-153725754-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153725754-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.488G>A	p.Arg163His	missense_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.488G>A	p.Arg163His	missense_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.488G>A	p.Arg163His	missense_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.488G>A	p.Arg163His	missense_variant	1/10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097568 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363288

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.: 26

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 14, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2021	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. Other missense substitutions at this codon (p.Arg163Pro, p.Arg163Leu, p.Arg163Gly) have been reported in individuals affected with X-linked adrenoleukodystrophy (PMID: 10980309, 25324868, 26227820). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with X-linked adrenoleukodystrophy (PMID: 7825602). ClinVar contains an entry for this variant (Variation ID: 372736). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 163 of the ABCD1 protein (p.Arg163His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2016	The R163H variant in the ABCD1 gene has been reported previously in association with X-linked adrenoleukodystrophy in a symptomatic female carrier (Ligtenberg et al., 1995). The R163H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R163H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (L158P, L160P, S161P, R163P, R163L, R163G) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R163H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2017

The p.R163H variant (also known as c.488G>A), located in coding exon 1 of the ABCD1 gene, results from a G to A substitution at nucleotide position 488. The arginine at codon 163 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in a symptomatic female with elevated very long chain fatty acids (Ligtenberg MJ et al. Am. J. Hum. Genet., 1995 Jan;56:44-50). Based on structural analysis, this variant disrupts transmembrane domain structure and changes the binding affinity with PEX19 (Aller SG et al. Science, 2009 Mar;323:1718-22; Perez C et al. Nature, 2015 Aug;524:433-8; Li N et al. Cell, 2017 Jan;168:101-110.e10; Morgan JL et al. Structure, 2017 Mar;25:522-529). 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. -

ABCD1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

The ABCD1 c.488G>A variant is predicted to result in the amino acid substitution p.Arg163His. This variant was reported in an individual with adrenoleukodystrophy (ALD) (Ligtenberg et al. 1995. PubMed ID: 7825602). Alternate nucleotide changes affecting the same amino acid (p.Arg163Pro, p.Arg163Leu, p.Arg163Gly, p.Arg163Cys) have been reported in individuals affected with ALD (Ohi et al. 2000. PubMed ID: 10980309; Jwa et al. 2014. PubMed ID: 25324868; Ogaki et al. 2015. PubMed ID: 26227820; Wiens et al. 2019. PubMed ID: 31074578). This variant occurs within the trans-membrane domain (TMD) in exon 1 where pathogenic variants are known to cluster (Chu et al. 2015. PubMed ID: 26454440; Kemp et al. 2001. PubMed ID: 11748843). This variant has not been reported in a large population database, indicating this variant is rare. The c.488G>A variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Loss of methylation at R163 (P = 0.0184);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
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

Other links and lift over

dbSNP: rs1057517954; hg19: chrX-152991209;