rs11146842

chrX-153743056-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):c.1850G>A(p.Arg617His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.13

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 16 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-153743056-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1850G>A	p.Arg617His	missense_variant	8/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.2150G>A	p.Arg717His	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1850G>A	p.Arg617His	missense_variant	8/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4478C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.25e-7 AC: 1 AN: 1081611 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352425

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000337

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 617 of the ABCD1 protein (p.Arg617His). 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 adrenomyeloneuropathy (AMN) and X-linked ALD and X-linked adrenoleukodystrophy (ALD) (PMID: 7581394, 8040304, 15800013, 21068741, 21700483, 26454440). In at least one individual the variant was observed to be de novo. This variant is also known as c.2236G>A. ClinVar contains an entry for this variant (Variation ID: 11312). 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%. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 7668254, 9425230, 17542813). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 10, 2019	This variant was identified as hemizygous -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 01, 2019	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2022	Functional studies demonstrate a damaging effect of R617H on gene product (Braiterman et al., 1998; Takahashi et al., 2007); 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: 11748843, 17542813, 8040304, 27766264, 7841445, 7668254, 12624723, 7581394, 15800013, 22479560, 26454440, 21068741, 29926352, 20859061, 21700483, 9425230) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 11, 2020	The ABCD1 c.1850G>A; p.Arg617His variant (rs11146842) is reported in the literature in multiple individuals with X-ALD, including at least one individual in which it was presumed de novo (Fanen 1994, see ALD database). 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, and functional studies in patient fibroblasts demonstrate decreased expression of the variant protein, likely due to proteosomal degradation (Takahashi 2007, Watkins 1995). Other alterations at this codon (p.Arg617Ser, p.Arg617Gly, p.Arg617Cys) have also been reported in individuals with X-ALD and are considered disease-causing (see ALD database). Based on available information, the p.Arg617His variant is considered pathogenic. References: Link to ALD database: http://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 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. Takahashi N et al. Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations. J Neurochem. 2007 Jun;101(6):1632-43. Watkins PA et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995;57(2):292-301. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		1.0		Loss of MoRF binding (P = 0.0152);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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: rs11146842; hg19: chrX-153008510;