rs11146842
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000033.4(ABCD1):c.1850G>A(p.Arg617His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000033.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1850G>A | p.Arg617His | missense_variant | 8/10 | ENST00000218104.6 | |
ABCD1 | XM_047441916.1 | c.2150G>A | p.Arg717His | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1850G>A | p.Arg617His | missense_variant | 8/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.72-4478C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 25
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.25e-7 AC: 1AN: 1081611Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 352425
GnomAD4 genome Cov.: 25
ClinVar
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 01, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 10, 2019 | This variant was identified as hemizygous - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 617 of the ABCD1 protein (p.Arg617His). 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 adrenomyeloneuropathy (AMN) and X-linked ALD and X-linked adrenoleukodystrophy (ALD) (PMID: 7581394, 8040304, 15800013, 21068741, 21700483, 26454440). In at least one individual the variant was observed to be de novo. This variant is also known as c.2236G>A. ClinVar contains an entry for this variant (Variation ID: 11312). 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%. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 7668254, 9425230, 17542813). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 11, 2020 | The ABCD1 c.1850G>A; p.Arg617His variant (rs11146842) is reported in the literature in multiple individuals with X-ALD, including at least one individual in which it was presumed de novo (Fanen 1994, see ALD database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 617 is highly conserved, and functional studies in patient fibroblasts demonstrate decreased expression of the variant protein, likely due to proteosomal degradation (Takahashi 2007, Watkins 1995). Other alterations at this codon (p.Arg617Ser, p.Arg617Gly, p.Arg617Cys) have also been reported in individuals with X-ALD and are considered disease-causing (see ALD database). Based on available information, the p.Arg617His variant is considered pathogenic. References: Link to ALD database: http://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Fanen P et al. Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene. J Clin Invest. 1994 Aug;94(2):516-20. Takahashi N et al. Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations. J Neurochem. 2007 Jun;101(6):1632-43. Watkins PA et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995;57(2):292-301. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 23, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2022 | Functional studies demonstrate a damaging effect of R617H on gene product (Braiterman et al., 1998; Takahashi et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11748843, 17542813, 8040304, 27766264, 7841445, 7668254, 12624723, 7581394, 15800013, 22479560, 26454440, 21068741, 29926352, 20859061, 21700483, 9425230) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 23, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at