ClinVar contains an entry for this variant (Variation ID: 162148). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked adrenoleukodystrophy (PMID: 15811009, 27489563). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg85Profs*110) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000033.4(ABCD1):c.253dup (p.Arg85fs)
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.
(3)
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
3
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.253dup (p.Arg85fs)
Variation ID: 162148 Accession: VCV000162148.8
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: Xq28 X: 153725514-153725515 (GRCh38) [ NCBI UCSC ] X: 152990969-152990970 (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 Jan 8, 2015 Feb 14, 2024 May 5, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000033.4:c.253dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000024.2:p.Arg85fs frameshift NC_000023.11:g.153725519dup NC_000023.10:g.152990974dup NG_009022.2:g.5652dup NG_023231.1:g.4232dup LRG_1017:g.5652dup LRG_1017t1:c.253dup LRG_1017p1:p.Arg85fs - Protein change
- R85fs
- Other names
- -
- Canonical SPDI
- NC_000023.11:153725514:CCCCC:CCCCCC
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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.
- -
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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. |
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| 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 (2) |
criteria provided, single submitter
|
May 5, 2022 | RCV000149556.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 2, 2015 | RCV000790677.4 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Dec 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000337944.3
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(May 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenoleukodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002134121.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 162148). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked … (more)
ClinVar contains an entry for this variant (Variation ID: 162148). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked adrenoleukodystrophy (PMID: 15811009, 27489563). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg85Profs*110) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 17, 2014)
|
no assertion criteria provided
Method: research
|
Adrenoleukodystrophy
(X-linked inheritance)
Affected status: yes, no
Allele origin:
germline
|
Faculty of Medicine, Iran University of Medical Sciences (IUMS)
Additional submitters:
Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences
Department of Neurology, Firoozgar Hospital, Iran University of Medical Sciences (IUMS)
Ata Genetics Laboratory
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences
Accession: SCV000196515.1
First in ClinVar: Jan 08, 2015 Last updated: Jan 08, 2015
Comments (2):
Among all 96 pedigree members, nineteen (fifteen male and four female) probands were affected and sixteen female were carriers. We have also detected β-thalassemia minor … (more)
Among all 96 pedigree members, nineteen (fifteen male and four female) probands were affected and sixteen female were carriers. We have also detected β-thalassemia minor in four females (two carriers, and two genetically unaffected). (less)
The first study to report a novel ABCD1 variant that causes adrenoleukodystrophy in a large, consanguineous Iranian pedigree.
|
Comment:
Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling … (more)
Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities with subsequent elevated prevalence. Unexpectedly, there exist childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes of ALD in our pedigree with the same variant. X-ALD also occurred significantly more in our studied Iranian pedigree compared to its reported prevalence (Odd Ratio 4249.7500, 95% CI 224.6575 to 80390.7075, p-value< 0.0001). (less)
Observation 1:
Number of individuals with the variant: 19
Clinical Features:
childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease (present)
Age: 3-90 years
Sex: mixed
Ethnicity/Population group: Causasians
Geographic origin: Iran;Lorestan province;Borujerd city
Tissue: peripheral blood leukocytes
Observation 2:
Number of individuals with the variant: 16
Sex: female
Ethnicity/Population group: Causasians
Geographic origin: Iran;Lorestan province;Borujerd city
Tissue: peripheral blood leukocytes
|
Comment:
Comment:
Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities with subsequent elevated prevalence. Unexpectedly, there exist childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes of ALD in our pedigree with the same variant. X-ALD also occurred significantly more in our studied Iranian pedigree compared to its reported prevalence (Odd Ratio 4249.7500, 95% CI 224.6575 to 80390.7075, p-value< 0.0001).
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:
ClinVar contains an entry for this variant (Variation ID: 162148). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked adrenoleukodystrophy (PMID: 15811009, 27489563). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg85Profs*110) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). For these reasons, this variant has been classified as Pathogenic.
Comment:
Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities with subsequent elevated prevalence. Unexpectedly, there exist childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes of ALD in our pedigree with the same variant. X-ALD also occurred significantly more in our studied Iranian pedigree compared to its reported prevalence (Odd Ratio 4249.7500, 95% CI 224.6575 to 80390.7075, p-value< 0.0001).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| An ABCD1 Mutation (c.253dupC) Caused Diverse Phenotypes of Adrenoleukodystrophy in an Iranian Consanguineous Pedigree. | Mehrpour M | Journal of molecular and genetic medicine : an international journal of biomedical research | 2016 | PMID: 27489563 |
| Clinical and genetic aspects in twelve Korean patients with adrenomyeloneuropathy. | Park HJ | Yonsei medical journal | 2014 | PMID: 24719134 |
| Multiple endocrine disorders associated with adrenomyeloneuropathy and a novel mutation of the ABCD1 gene. | Triantafyllou P | Pediatric neurology | 2014 | PMID: 24685009 |
| Parallel assessment of globin lentiviral transfer in induced pluripotent stem cells and adult hematopoietic stem cells derived from the same transplanted β-thalassemia patient. | Tubsuwan A | Stem cells (Dayton, Ohio) | 2013 | PMID: 23712774 |
| Impaired very long-chain acyl-CoA β-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. | Wiesinger C | The Journal of biological chemistry | 2013 | PMID: 23671276 |
| Gene therapy on demand: site specific regulation of gene therapy. | Jazwa A | Gene | 2013 | PMID: 23566848 |
| A Novel Double Mutation in the ABCD1 Gene in a Patient with X-linked Adrenoleukodystrophy: Analysis of the Stability and Function of the Mutant ABCD1 Protein. | Morita M | JIMD reports | 2013 | PMID: 23430809 |
| X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients. | Amorosi CA | PloS one | 2012 | PMID: 23300730 |
| Peroxisomal ABC transporters: structure, function and role in disease. | Morita M | Biochimica et biophysica acta | 2012 | PMID: 22366764 |
| Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity. | Wu C | Frontiers of medicine | 2011 | PMID: 22198747 |
| Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India. | Kumar N | PloS one | 2011 | PMID: 21966424 |
| Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. | Miller WP | Blood | 2011 | PMID: 21586746 |
| Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. | Kemp S | British journal of pharmacology | 2011 | PMID: 21488864 |
| Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. | Simpson S Jr | Journal of neurology, neurosurgery, and psychiatry | 2011 | PMID: 21478203 |
| Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. | Singh I | Brain pathology (Zurich, Switzerland) | 2010 | PMID: 20626745 |
| Stem cells in genetic myelin disorders. | Kemp K | Regenerative medicine | 2010 | PMID: 20455653 |
| Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders. | Persons DA | Hematology. American Society of Hematology. Education Program | 2009 | PMID: 20008255 |
| X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. | Berger J | Biochimica et biophysica acta | 2006 | PMID: 16949688 |
| The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy (X-ALD). | Ping LL | Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences | 2006 | PMID: 16415970 |
| Natural history of X-linked adrenoleukodystrophy in Japan. | Suzuki Y | Brain & development | 2005 | PMID: 16023551 |
| Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. | Dubey P | The Journal of pediatrics | 2005 | PMID: 15812458 |
| 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 |
| Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy. | Asheuer M | Human molecular genetics | 2005 | PMID: 15800013 |
| Novel insertion 496_497insG creating a stop codon D194X in a Chinese family with X-Linked adrenoleukodystrophy. | Mak CM | Hormone research | 2005 | PMID: 15564782 |
| Method for measurement of peroxisomal very-long-chain fatty acid beta-oxidation in human skin fibroblasts using stable-isotope-labeled tetracosanoic acid. | Kemp S | Clinical chemistry | 2004 | PMID: 15388659 |
| Nonsense-mediated decay approaches the clinic. | Holbrook JA | Nature genetics | 2004 | PMID: 15284851 |
| Mouse models and genetic modifiers in X-linked adrenoleukodystrophy. | Heinzer AK | Advances in experimental medicine and biology | 2003 | PMID: 14713218 |
| Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. | Loes DJ | Neurology | 2003 | PMID: 12913200 |
| ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. | Kemp S | Human mutation | 2001 | PMID: 11748843 |
| Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. | Bezman L | Annals of neurology | 2001 | PMID: 11310629 |
| Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. | van Geel BM | Annals of neurology | 2001 | PMID: 11220738 |
| X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. | Melhem ER | AJNR. American journal of neuroradiology | 2000 | PMID: 10815658 |
| Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. | Moser AB | Annals of neurology | 1999 | PMID: 9894883 |
| Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. | Bezman L | American journal of medical genetics | 1998 | PMID: 9556301 |
| Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. | Korenke GC | Annals of neurology | 1996 | PMID: 8773611 |
| Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. | Ligtenberg MJ | American journal of human genetics | 1995 | PMID: 7825602 |
| MR findings in adult-onset adrenoleukodystrophy. | Kumar AJ | AJNR. American journal of neuroradiology | 1995 | PMID: 7677014 |
| Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins. | Sobue G | Annals of neurology | 1994 | PMID: 7998779 |
| cDNA sequence of Aldgh, the mouse homolog of the X-linked adrenoleukodystrophy gene. | Sarde CO | Mammalian genome : official journal of the International Mammalian Genome Society | 1994 | PMID: 7894167 |
| X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes. | Berger J | Biochemical and biophysical research communications | 1994 | PMID: 7811247 |
| Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. | Mosser J | Nature | 1993 | PMID: 8441467 |
| Profiles of very-long-chain fatty acids in plasma, fibroblasts, and blood cells in Zellweger syndrome, X-linked adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata. | Schutgens RB | Clinical chemistry | 1993 | PMID: 8353949 |
| Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy. | Maestri NE | American journal of medical genetics | 1992 | PMID: 1481812 |
| Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes. | Singh I | Pediatric research | 1984 | PMID: 6728562 |
| Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. | Moser HW | Neurology | 1981 | PMID: 7202134 |
| Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. | Migeon BR | Proceedings of the National Academy of Sciences of the United States of America | 1981 | PMID: 6795626 |
| http://www.x-ald.nl/mutations-gene/mutations-in-abcd1 | - | - | - | - |
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Text-mined citations for rs713993050 ...
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.