Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically enriched in patients compared to ethnically matched controls. Results on protein functions were inconclusive.
ClinVar Genomic variation as it relates to human health
NM_000033.4(ABCD1):c.1166G>A (p.Arg389His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000033.4(ABCD1):c.1166G>A (p.Arg389His)
Variation ID: 281336 Accession: VCV000281336.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 153736196 (GRCh38) [ NCBI UCSC ] X: 153001650 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 2, 2018 Feb 14, 2024 Sep 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000033.4:c.1166G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000024.2:p.Arg389His missense NC_000023.11:g.153736196G>A NC_000023.10:g.153001650G>A NG_009022.2:g.16329G>A LRG_1017:g.16329G>A LRG_1017t1:c.1166G>A LRG_1017p1:p.Arg389His P33897:p.Arg389His - Protein change
- R389H
- Other names
- -
- Canonical SPDI
- NC_000023.11:153736195:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ABCD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1529 | 1775 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000268436.16 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 27, 2023 | RCV000984141.13 | |
|
ABCD1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 6, 2023 | RCV003391027.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000612225.3
First in ClinVar: Dec 06, 2016 Last updated: Jan 19, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically enriched in patients compared to ethnically matched controls. Results on protein functions were inconclusive. (less)
|
|
|
Pathogenic
(Jun 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700868.2
First in ClinVar: Apr 02, 2018 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Aug 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenoleukodystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361104.2
First in ClinVar: Jun 22, 2020 Last updated: Sep 08, 2021 |
Comment:
Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in 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 183351 control chromosomes. c.1166G>A has been reported in the literature in multiple individuals affected with ABCD1-related diseases (Coll_2005, Kemp_1995, Kok_1995, Hodapp_2006, Engelen_2014, Matteson_2021). These data indicate that the variant is very likely to be associated with disease. In functional studies compared to controls, the variant showed less than 50% of peroxisomal beta-oxidation activity and approximately 40% of ALDP protein levels (Schackmann_2016, Zhang_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenoleukodystrophy
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045819.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004031738.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 8892025, 34649108, 16401743, 7668254, 21476988, 9242200, 7581394, 15811009, 7825602, 30732635, 27067449, 31526374, 24480483, 24719134, 34946879, 10551832, 27535533) (less)
|
|
|
Pathogenic
(Feb 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ABCD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120525.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCD1 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple patients with X-linked adrenoleukodystrophy … (more)
The ABCD1 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple patients with X-linked adrenoleukodystrophy (Kok et al. 1995. PubMed ID: 7581394; Ligtenberg et al. 1995. PubMed ID: 7825602; Schackmann et al. 2016. PubMed ID: 27067449). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Sep 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenoleukodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001198016.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 8566952, 15811009, 22479560). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 281336). This missense change has been observed in individuals with ABCD1-related disease (PMID: 7581394, 7825602, 15811009, 24719134). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCD1 protein (p.Arg389His). (less)
|
|
|
Likely pathogenic
(May 09, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Adrenoleukodystrophy
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132113.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743456.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958731.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
Comment:
Comment:
Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in 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 183351 control chromosomes. c.1166G>A has been reported in the literature in multiple individuals affected with ABCD1-related diseases (Coll_2005, Kemp_1995, Kok_1995, Hodapp_2006, Engelen_2014, Matteson_2021). These data indicate that the variant is very likely to be associated with disease. In functional studies compared to controls, the variant showed less than 50% of peroxisomal beta-oxidation activity and approximately 40% of ALDP protein levels (Schackmann_2016, Zhang_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); 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: 8892025, 34649108, 16401743, 7668254, 21476988, 9242200, 7581394, 15811009, 7825602, 30732635, 27067449, 31526374, 24480483, 24719134, 34946879, 10551832, 27535533)
Comment:
The ABCD1 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple patients with X-linked adrenoleukodystrophy (Kok et al. 1995. PubMed ID: 7581394; Ligtenberg et al. 1995. PubMed ID: 7825602; Schackmann et al. 2016. PubMed ID: 27067449). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 8566952, 15811009, 22479560). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 281336). This missense change has been observed in individuals with ABCD1-related disease (PMID: 7581394, 7825602, 15811009, 24719134). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCD1 protein (p.Arg389His).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically enriched in patients compared to ethnically matched controls. Results on protein functions were inconclusive.
Comment:
Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in 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 183351 control chromosomes. c.1166G>A has been reported in the literature in multiple individuals affected with ABCD1-related diseases (Coll_2005, Kemp_1995, Kok_1995, Hodapp_2006, Engelen_2014, Matteson_2021). These data indicate that the variant is very likely to be associated with disease. In functional studies compared to controls, the variant showed less than 50% of peroxisomal beta-oxidation activity and approximately 40% of ALDP protein levels (Schackmann_2016, Zhang_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); 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: 8892025, 34649108, 16401743, 7668254, 21476988, 9242200, 7581394, 15811009, 7825602, 30732635, 27067449, 31526374, 24480483, 24719134, 34946879, 10551832, 27535533)
Comment:
The ABCD1 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple patients with X-linked adrenoleukodystrophy (Kok et al. 1995. PubMed ID: 7581394; Ligtenberg et al. 1995. PubMed ID: 7825602; Schackmann et al. 2016. PubMed ID: 27067449). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 8566952, 15811009, 22479560). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 281336). This missense change has been observed in individuals with ABCD1-related disease (PMID: 7581394, 7825602, 15811009, 24719134). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCD1 protein (p.Arg389His).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up. | Matteson J | International journal of neonatal screening | 2021 | PMID: 33920672 |
| Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics. | Schackmann MJ | Molecular genetics and metabolism | 2016 | PMID: 27067449 |
| Clinical and genetic aspects in twelve Korean patients with adrenomyeloneuropathy. | Park HJ | Yonsei medical journal | 2014 | PMID: 24719134 |
| X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. | Engelen M | Brain : a journal of neurology | 2014 | PMID: 24480483 |
| Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy. | Pereira Fdos S | PloS one | 2012 | PMID: 22479560 |
| Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression. | Zhang X | The Biochemical journal | 2011 | PMID: 21476988 |
| Phenotype prediction of non-synonymous single-nucleotide polymorphisms in human ATP-binding cassette transporter genes. | Wang LL | Basic & clinical pharmacology & toxicology | 2011 | PMID: 20849526 |
| Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. | Hodapp JA | Archives of neurology | 2006 | PMID: 16401743 |
| X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females. | Coll MJ | Clinical genetics | 2005 | PMID: 15811009 |
| ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. | Kemp S | Human mutation | 2001 | PMID: 11748843 |
| Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters. | Liu LX | The Journal of biological chemistry | 1999 | PMID: 10551832 |
| Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings. | Korenke GC | European journal of endocrinology | 1997 | PMID: 9242200 |
| ALDP expression in fibroblasts of patients with X-linked adrenoleukodystrophy. | Kemp S | Journal of inherited metabolic disease | 1996 | PMID: 8892025 |
| Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. | Krasemann EW | Human genetics | 1996 | PMID: 8566952 |
| Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. | Ligtenberg MJ | American journal of human genetics | 1995 | PMID: 7825602 |
| Altered expression of ALDP in X-linked adrenoleukodystrophy. | Watkins PA | American journal of human genetics | 1995 | PMID: 7668254 |
| Mutational analysis of patients with X-linked adrenoleukodystrophy. | Kok F | Human mutation | 1995 | PMID: 7581394 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCD1 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs886044777 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.