chrX-153740155-C-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000033.4(ABCD1):c.1552C>T(p.Arg518Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000033.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ABCD1 | NM_000033.4 | MANE Select | c.1552C>T | p.Arg518Trp | missense | Exon 6 of 10 | NP_000024.2 | ||
| ABCD1 | NM_001440747.1 | c.1852C>T | p.Arg618Trp | missense | Exon 7 of 11 | NP_001427676.1 | |||
| PLXNB3-AS1 | NR_199693.1 | n.90-1577G>A | intron | N/A |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ABCD1 | ENST00000218104.6 | TSL:1 MANE Select | c.1552C>T | p.Arg518Trp | missense | Exon 6 of 10 | ENSP00000218104.3 | ||
| ABCD1 | ENST00000443684.2 | TSL:3 | n.555C>T | non_coding_transcript_exon | Exon 5 of 6 | ||||
| PLXNB3-AS1 | ENST00000434284.1 | TSL:3 | n.72-1577G>A | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:6
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. This variant disrupts the p.Arg518 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10190819, 12175782, 15811009, 16087056, 21068741, 23419472, 23566833, 26260157). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 11307). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 8651290, 12175782, 20661612, 26454440). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 518 of the ABCD1 protein (p.Arg518Trp).
ABCD1 NM_000033.3 exon 6 p.Arg518Trp (c.1552C>T): This variant has been reported in the literature in at least 3 individuals with a clinical diagnosis or features of adrenoleukodystrophy (ALD), segregating with disease in at least 1 affected family member (Fanen 1994 PMID:8040304, Guettsches 2010 PMID:20195870, Shimozawa 2011 PMID:21068741). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:11307). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this same codon (p.Arg518Pro, p.Arg518Gly, p.Arg518Gln) have been reported in the literature, suggesting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Variant summary: ABCD1 c.1552C>T (p.Arg518Trp) results in a non-conservative amino acid change located in the AAA+ ATPase 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 177823 control chromosomes (gnomAD and publication). c.1552C>T has been reported in the literature in multiple individuals affected with Adrenoleukodystrophy including symptomatic female carriers (Chu_2015, Fanen_1994, Feigenbaum_1996, Guettsches_2010, Guimaraes_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
not provided Pathogenic:2
X-linked spondyloepimetaphyseal dysplasia Pathogenic:1
The ABCD1 p.Arg518Trp variant was identified in 5 of 318 proband chromosomes (frequency: 0.02) from individuals or families with X-linked adrenoleukodystrophy, and was not identified in 200 control chromosomes from healthy individuals (Chu 2015, Fanen 1994, Matsukawa 2010, Feigenbaum 1996). The variant was also found in case study by Guettsches (2010) in two symptomatic adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) female carriers. The son of one of the carriers died of ALD at age of 9. The variant was identified in dSNP (rs128624224) as "With Pathogenic allele", ClinVar (classified as pathogenic by OMIM and EGL genetic Diagnistics), the ALD Mutation Database (as pathogenic, identified in 19 ALD patients; no detectable ALDP in patient cells) and LOVD (as likely pathogenic). 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 protein analysis study by Feigenbaum (1996) identifies the variant resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. The p.Arg518 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at