X-153743055-C-G

Position:

• chrX-153743055-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):​c.1849C>G​(p.Arg617Gly) variant causes a missense change. 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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: 24)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 14 ACMG points.

• PS1: Transcript NM_000033.4 (ABCD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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-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-153743055-C-G is Pathogenic according to our data. Variant chrX-153743055-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 996792.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1849C>G	p.Arg617Gly	missense_variant	8/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.2149C>G	p.Arg717Gly	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1849C>G	p.Arg617Gly	missense_variant	8/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4477G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Feb 01, 2021

- -

ABCD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

The ABCD1 c.1849C>G variant is predicted to result in the amino acid substitution p.Arg617Gly. This variant (also known as 2235C>G) has been reported in individuals with adrenoleukodystrophy (Krasemann et al. 1996. PubMed ID: 8566952; Lan et al. 2011. PubMed ID: 21300044; Mao et al. 2022. PubMed ID: 34997422; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). This variant has not been reported in a large population database, indicating this variant is rare. Other missense variants affecting this amino acid (p.Arg617Cys, p.Arg617His, p.Arg617Leu, p.Arg617Ser) have also been reported in individuals with adrenoleukodystrophy (Fanen et al. 1994. PubMed ID: 8040304; Coll et al. 2005. PubMed ID: 15811009; Figure 1, Liu et al. 2021. PubMed ID: 34826210). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of MoRF binding (P = 0.0198);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		1.0

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; COSMIC: COSV99497448; COSMIC: COSV99497448;