chrX-153726089-C-T

Position:

• chrX-153726089-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The ENST00000218104.6(ABCD1):​c.823C>T​(p.Arg275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,071,770 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: ABCD1 ENST00000218104.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 0.258

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000218104.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153726090-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2732781.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant X-153726089-C-T is Pathogenic according to our data. Variant chrX-153726089-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384589.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.823C>T	p.Arg275Trp	missense_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.823C>T	p.Arg275Trp	missense_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.823C>T	p.Arg275Trp	missense_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.823C>T	p.Arg275Trp	missense_variant	1/10	1	NM_000033.4	ENSP00000218104	P1
ABCD1	ENST00000370129.4	c.268C>T	p.Arg90Trp	missense_variant	1/2	2		ENSP00000359147

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.00000740 AC: 1 AN: 135103 Hom.: 0 AF XY: 0.0000274 AC XY: 1 AN XY: 36521

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000373 AC: 4 AN: 1071770 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 1 AN XY: 344666

Gnomad4 AFR exome AF: 0.0000387

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ExAC AF: 0.0000335 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Sep 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the ABCD1 protein (p.Arg275Trp). 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: 31074578; Invitae). It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 384589). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2024	Variant summary: ABCD1 c.823C>T (p.Arg275Trp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-06 in 135103 control chromosomes. c.823C>T has been reported in the literature in at least 2 individuals affected with clinical features of ABCD1-related conditions and multiple individuals testing positive for X-ALD on newborn screening (example, Beil_2023, Weins_2019, Tang_2024, Matteson_2021). Further, multiple variants have been reportedly associated with disease in this region of the protein, suggesting a possible hotspot. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33920672, 31074578, 37977233). ClinVar contains an entry for this variant (Variation ID: 384589). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2024	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: 37977233, 31074578, 33920672) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 27, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2017

The p.R275W variant (also known as c.823C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 823. The arginine at codon 275 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

ABCD1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The ABCD1 c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant has been reported in the hemizygous state in multiple individuals with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Wiens et al 2019. PubMed ID: 31074578; Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). However, this variant has also been reported in the hemizygous state in unaffected individuals (Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent, including one hemizygote, in gnomAD. An alternate nucleotide affecting the same amino acid (p.Arg275Pro), has been reported in the hemizygous state in an individual with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Priestley et al. 2022. PubMed ID: 35466195). Although we suspect that the c.823C>T (p.Arg275Trp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
FATHMM_MKL	Benign	0.45	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		1.0	D;.
Vest4		0.47
MutPred		0.56		Loss of disorder (P = 0.0053);.;
MVP		1.0
MPC		1.6
ClinPred		0.92	D
GERP RS		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.96

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: rs782083931; hg19: chrX-152991544;