rs782041940
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000033.4(ABCD1):c.1900G>A(p.Ala634Thr) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A634V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000033.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1900G>A | p.Ala634Thr | missense_variant | 9/10 | ENST00000218104.6 | |
ABCD1 | XM_047441916.1 | c.2200G>A | p.Ala734Thr | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1900G>A | p.Ala634Thr | missense_variant | 9/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.72-4677C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1AN: 1094646Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1AN XY: 361268
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 20, 2022 | This variant was identified as hemizygous._x000D_ Criteria applied: PS4_MOD, PM2_SUP, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 634 of the ABCD1 protein (p.Ala634Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy (PMID: 35076462; external communication). ClinVar contains an entry for this variant (Variation ID: 282253). 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%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Mar 28, 2019 | This ABCD1 variant is absent from large population datasets and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classifies it as likely pathogenic and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this variant may create a potential cryptic splice site, however, its effect on splicing has not been studied experimentally to our knowledge. The clinical significance of c.1900G>A is uncertain at this time. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 12, 2020 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 18, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 24, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2023 | Reported in a male with a borderline newborn screen for X-ALD in the published literature; Classified as a variant of uncertain significance in two individuals with a positive newborn screen for X-ALD (Matteson et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34946879, 35076462, 33920672, 34506099) - |
ABCD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 18, 2023 | The ABCD1 c.1900G>A variant is predicted to result in the amino acid substitution p.Ala634Thr. This variant was reported in individuals with borderline adrenoleukodystrophy, but was classified as a variant of uncertain significance (Burton et al. 2022. PubMed ID: 35076462; Supplemental table, Matteson et al. 2021. PubMed ID: 33920672; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). Functional studies in fibroblasts suggest this variant impacts ABCD1 activity (van de Stadt et al. 2021. PubMed ID: 34946879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While we suspect that this variant could be pathogenic, at this time we interpret its clinical significance as uncertain due to insufficient functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at