Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000434855 | SCV000525476 | likely pathogenic | not provided | 2017-08-03 | criteria provided, single submitter | clinical testing | The R275W variant in the ABCD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R275W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E271K, A273E, R274P, K276E, G277R, G277W, G277E, L279P, R280C, R280L) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy or with adrenomyeloneuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R275W variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. |
ARUP Laboratories, |
RCV000507685 | SCV000602346 | uncertain significance | not specified | 2017-03-27 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000695726 | SCV000824241 | likely pathogenic | Adrenoleukodystrophy | 2024-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the ABCD1 protein (p.Arg275Trp). 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: 31074578; Invitae). It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 384589). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Molecular Diagnostics Laboratory, |
RCV000695726 | SCV000891168 | likely pathogenic | Adrenoleukodystrophy | 2017-09-19 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000434855 | SCV002023962 | likely pathogenic | not provided | 2023-07-06 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000695726 | SCV002045758 | likely pathogenic | Adrenoleukodystrophy | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002411343 | SCV002676091 | uncertain significance | Inborn genetic diseases | 2017-07-17 | criteria provided, single submitter | clinical testing | The p.R275W variant (also known as c.823C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 823. The arginine at codon 275 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Prevention |
RCV003902547 | SCV004721300 | uncertain significance | ABCD1-related condition | 2023-12-20 | criteria provided, single submitter | clinical testing | The ABCD1 c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant has been reported in the hemizygous state in multiple individuals with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Wiens et al 2019. PubMed ID: 31074578; Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). However, this variant has also been reported in the hemizygous state in unaffected individuals (Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent, including one hemizygote, in gnomAD. An alternate nucleotide affecting the same amino acid (p.Arg275Pro), has been reported in the hemizygous state in an individual with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Priestley et al. 2022. PubMed ID: 35466195). Although we suspect that the c.823C>T (p.Arg275Trp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |