chrX-153743055-C-T

Position:

• chrX-153743055-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1849C>T​(p.Arg617Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000924 in 1,082,491 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.70

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]

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

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153743056-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-153743055-C-T is Pathogenic according to our data. Variant chrX-153743055-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153743055-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1849C>T	p.Arg617Cys	missense_variant	8/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.2149C>T	p.Arg717Cys	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1849C>T	p.Arg617Cys	missense_variant	8/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4477G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082491 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352789

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 617 of the ABCD1 protein (p.Arg617Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked adrenoleukodystrophy and Addison's disease (PMID: 7825602, 8040304, 8566952, 15811009, 16087056, 17029209). ClinVar contains an entry for this variant (Variation ID: 11313). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg617 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581394, 8040304, 9425230, 17542813, 21068741, 21700483). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 22, 2021	ACMG codes:PS4, PM1, PM2, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 28, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 04, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 22, 2018	This variant was identified as hemizygous -
Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jan 08, 2021	Criteria Codes: PS3 PS4_Mod PM2 PM5 PP3 PP4 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2019	The ABCD1 c.1849C>T; p.Arg617Cys variant (rs4010613) is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (X-ALD) (Coll 2005, Fanen 1994, Kemp 2001, Krasemann 1996, Lan 2011, Ligtenberg 1995, Pan 2005). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 617 is highly conserved, it occurs in the ABCD1 nucleotide binding fold (Fanen 1994), and functional studies of patient fibroblasts with this variant suggest loss of protein expression (Kemp 2001). Additionally, other amino acid substitutions at this codon (Gly, His, Leu) have been reported in individuals with X-ALD and are considered disease-causing (Coll 2005, Fanen 1994, Kemp 2001, Krasemann 1996, Lan 2011, Pan 2005). Based on available information, the p.Arg617Cys variant is considered to be pathogenic. References: 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. Fanen P et al. Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene. J Clin Invest. 1994 Aug;94(2):516-20. Kemp S et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001 Dec;18(6):499-515. Krasemann EW et al. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996 Feb;97(2):194-7. Lan F et al. Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations. Clin Chim Acta. 2011 May 12;412(11-12):970-4. Ligtenberg MJ et al. Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am J Hum Genet. 1995 Jan;56(1):44-50. Pan H et al. ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy. Pediatr Neurol. 2005 Aug;33(2):114-20. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		1.0		Loss of MoRF binding (P = 0.0084);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
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: rs4010613; hg19: chrX-153008509;