chrX-153726104-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000033.4(ABCD1):c.838C>T(p.Arg280Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,067,632 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 (★★).
Frequency
Genomes: not found (cov: 26)
Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )
Consequence
ABCD1
NM_000033.4 missense
NM_000033.4 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 4.46
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant X-153726104-C-T is Pathogenic according to our data. Variant chrX-153726104-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.838C>T | p.Arg280Cys | missense_variant | 1/10 | ENST00000218104.6 | NP_000024.2 | |
ABCD1 | XM_047441916.1 | c.838C>T | p.Arg280Cys | missense_variant | 1/11 | XP_047297872.1 | ||
ABCD1 | XM_047441917.1 | c.838C>T | p.Arg280Cys | missense_variant | 1/8 | XP_047297873.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.838C>T | p.Arg280Cys | missense_variant | 1/10 | 1 | NM_000033.4 | ENSP00000218104.3 | ||
ABCD1 | ENST00000370129.4 | c.283C>T | p.Arg95Cys | missense_variant | 1/2 | 2 | ENSP00000359147.3 |
Frequencies
GnomAD3 genomes Cov.: 26
GnomAD3 genomes
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26
GnomAD3 exomes AF: 0.0000155 AC: 2AN: 128935Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 33885
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GnomAD4 exome AF: 0.00000187 AC: 2AN: 1067632Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 342504
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GnomAD4 genome Cov.: 26
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the ABCD1 protein (p.Arg280Cys). 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: 11748843, 15811009; Invitae; https//adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). ClinVar contains an entry for this variant (Variation ID: 35643). 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.Arg280 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 11798073), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29443243, 11748843, 33920672, 35466195, 35076462, 36076658, 15811009) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 25, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 18, 2020 | The ABCD1 c.838C>T; p.Arg280Cys variant (rs193922098) is reported in several individuals with X-linked adrenoleukodystrophy and increased very-long-chain fatty acids (see link to ABCD1 variant database, Coll 2005, Isaacs 2014). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 35643) and is reported in the general population in 2 out of 128,935 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 280 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Link to ABCD1 database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 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. Isaacs D et al. Adult-onset Adrenoleukodystrophy Presenting After Chemotherapy: No Black and White Matter. Neurol Clin Pract. 2014 Apr;4(2):168-170. - |
History of neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2013 | - - |
ABCD1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2023 | The ABCD1 c.838C>T variant is predicted to result in the amino acid substitution p.Arg280Cys. This variant has been reported in multiple unrelated individuals with adrenoleukodystrophy (Kemp et al. 2001. PubMed ID: 11748843; Coll et al. 2005. PubMed ID: 15811009; Isaacs et al. 2014. PubMed ID: 29443243). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-152991559-C-T). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at