ClinVar Genomic variation as it relates to human health
NM_000033.4(ABCD1):c.896A>G (p.His299Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000033.4(ABCD1):c.896A>G (p.His299Arg)
Variation ID: 834266 Accession: VCV000834266.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 153726162 (GRCh38) [ NCBI UCSC ] X: 152991617 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 15, 2020 Feb 7, 2023 Dec 22, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000033.4:c.896A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000024.2:p.His299Arg missense NC_000023.11:g.153726162A>G NC_000023.10:g.152991617A>G NG_009022.2:g.6295A>G NG_023231.1:g.3585T>C LRG_1017:g.6295A>G LRG_1017t1:c.896A>G LRG_1017p1:p.His299Arg - Protein change
- H299R
- Other names
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- Canonical SPDI
- NC_000023.11:153726161:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- unknown functional consequence
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.0E0
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1495 | 1734 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2021 | RCV001034913.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001843369.1 |
Submissions - Germline
Classification
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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
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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
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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
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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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Uncertain significance
(Apr 01, 2021)
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criteria provided, single submitter
Method: research
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not specified
(X-linked recessive inheritance)
Affected status: no
Allele origin:
inherited
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Human Genetics Laboratory, Faculty of Medicine of Tunis
Accession: SCV002102484.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Number of individuals with the variant: 3
Sex: male
Ethnicity/Population group: North Africa
Geographic origin: Tunisia
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Uncertain significance
(Jun 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Adrenoleukodystrophy
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767615.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. There are multiple Loss of Function variants along the ABCD1 gene (Decipher). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Mutant adrenoleukodystrophy protein (ALDP) has been hypothesized to exert a dominant negative effect through the formation of non-functional heterodimers with the wild type ALDP (PMID: 11063720). (N) 0109 - This gene is known to be associated with X-linked recessive disease. However, female carriers have been also reported to be symptomatic (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v3 (66 Heterozygotes, 26 Hemizygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is in the ABCD1 Transmembrane-1 Domain (Protein Data Bank). (N) 0710 - Comparable variants have some previous evidence for being benign. The p.His299Tyr variant was previously identified in 1 individual with adrenoleukodystrophy but was classified as a false positive due to the number of hemizygotes present in the population. (B) 0808 - Previous reports of pathogenicity are conflicting. The variant has been classified as a Variant of Uncertain Significance in ClinVar and LOVD but has also been classified as Pathogenic in the ALD mutation database. (N) 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1007 - No published functional evidence has been identified for this variant literature. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Uncertain significance
(Dec 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adrenoleukodystrophy
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782211.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adrenoleukodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001198216.2
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces histidine with arginine at codon 299 of the ABCD1 protein (p.His299Arg). The histidine residue is highly conserved and there is a … (more)
This sequence change replaces histidine with arginine at codon 299 of the ABCD1 protein (p.His299Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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unknown functional consequence
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Human Genetics Laboratory, Faculty of Medicine of Tunis
Accession: SCV002102484.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome. | Kerkeni N | Journal of clinical neurology (Seoul, Korea) | 2022 | PMID: 35196747 |
Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy. | Unterrainer G | Human molecular genetics | 2000 | PMID: 11063720 |
Text-mined citations for rs782430461 ...
HelpRecord last updated Feb 07, 2023
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.