rs128624218
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000033.4(ABCD1):c.796G>A(p.Gly266Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000925 in 1,081,351 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 26)
Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )
Consequence
ABCD1
NM_000033.4 missense
NM_000033.4 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 9.58
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a domain ABC transmembrane type-1 (size 292) in uniprot entity ABCD1_HUMAN there are 43 pathogenic changes around while only 0 benign (100%) in NM_000033.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-153726062-G-A is Pathogenic according to our data. Variant chrX-153726062-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153726062-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ABCD1 | NM_000033.4 | c.796G>A | p.Gly266Arg | missense_variant | 1/10 | ENST00000218104.6 | NP_000024.2 | |
| ABCD1 | XM_047441916.1 | c.796G>A | p.Gly266Arg | missense_variant | 1/11 | XP_047297872.1 | ||
| ABCD1 | XM_047441917.1 | c.796G>A | p.Gly266Arg | missense_variant | 1/8 | XP_047297873.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
26
GnomAD4 exome AF: 9.25e-7 AC: 1AN: 1081351Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 350685
GnomAD4 exome
AF:
AC:
1
AN:
1081351
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
350685
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
26
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2018 | Variant summary: ABCD1 c.796G>A (p.Gly266Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 148143 control chromosomes (gnomAD). c.796G>A has been reported in the literature in multiple individuals affected with Adrenoleukodystrophy (Fuchs_1994, Ligtenber_1995, Takano_1999, Asheuer_2005, Pan_2005, Guimaraes_2002). These data indicate that the variant is very likely to be associated with disease. One publication reports that mRNA and protein levels are normal for ABCD1-G266R (Guimaraes_2002), although another publication, Kumar_2011, found the ALDP expression level in peripheral blood mononuclear cells in patients had 50-90% expression. Although, the implications of these levels have yet to be functionally assessed. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1994 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the ABCD1 protein (p.Gly266Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 7825602, 7849723, 14767898, 15192815, 15800013, 21068741, 21700483, 21966424). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11299). 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. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 12, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | ABCD1 NM_000033.3 exon 1 p.Gly266Arg (c.796G>A): This variant has been reported in the literature in several individuals with adrenoleukodystrophy, with one reported to be de novo (Fuchs 1994 PMID:7849723, Ligtenberg 1995 PMID:7825602, Pan 2004 PMID:14767898, Huang 2004 PMID:15192815, Asheuer 2005 PMID:15800013, Shimozawa 2011 PMID:21068741, Kumar 2011 PMID:21966424, Wang 2011 PMID:21700483). This variant is not present in large control databases but is present in ClinVar, with multiple labs classifying this variant as pathogenic (Variation ID:11299). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.796G>A (p.Gly266Arg) missense variant has been reported in multiple individuals affected with adrenoleukodystrophy (Shimozawa et al., 2011; Kumar et al., 2011) and in some of these individuals the variant occurred de novo (Wang et al., 2011). The p.Gly266Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic. The amino acid Gly at position 266 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly266Arg in ABCD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2022 | Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20661612, 11748843, 16415970, 17504626, 34826210, 21966424, 21068741, 15800013, 14767898, 7825602, 15192815, 10190819, 12175782, 16087056, 21300044, 23419472, 21700483, 31227335, 31418856, 34997422, 31069529, 27928321, 7849723) - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 10, 2017 | The p.G266R pathogenic mutation (also known as c.796G>A), located in coding exon 1 of the ABCD1 gene, results from a G to A substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This mutation was observed to segregate with disease in one large family in France (Fuchs S et al. Hum. Mol. Genet., 1994 Oct;3:1903-5). It has also been described as a de novo occurrence in multiple unrelated probands (Wang Y et al. Mol. Genet. Metab., 2011 Jun;104:160-6; Ohkuma Y et al. Neuroophthalmology, 2014 Oct;38:331-335). Furthermore, multiple different phenotypes have been observed among mutation carriers (Kumar N et al. PLoS ONE, 2011 Sep;6:e25094). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
X-linked spondyloepimetaphyseal dysplasia Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ABCD1 p.Gly266Arg variant was identified in 34 of 1408 proband chromosomes (frequency: 0.024) from individuals or families with X-linked adrenoleukodystrophy (Asheuer 2005, Guimaraes 2002, Horn 2013, Kumar 2011, Lan 2011, Matsukawa 2010, Shimozawa 2011, Wang 2011). The variant was also found in case study by Ohkuma (2014) in 10-year-old male with childhood cerebral X-linked ALD. The variant was identified in dSNP (rs128624218) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, OMIM and EGL genetic Diagnistics), the ALD Mutation Database (as pathogenic, identified in 33 ALD patients; normal ALDP level in patient cells but non-functional), and LOVD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant did not have any effect on protein stability in experimental study by Kawaguchi (2016) indicating that this amino acid residue is likely critical for the protein function as it was one of the most common ABCD1 mutations seen in patients with ALD in the literature. The p.Gly266 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
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
MutPred
Gain of MoRF binding (P = 0.0171);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at