ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp)
Variation ID: 203584 Accession: VCV000203584.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7224010 (GRCh38) [ NCBI UCSC ] 17: 7127329 (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 Sep 30, 2017 Jun 17, 2024 Mar 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1375C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Arg459Trp missense NM_001033859.3:c.1309C>T NP_001029031.1:p.Arg437Trp missense NM_001270447.2:c.1444C>T NP_001257376.1:p.Arg482Trp missense NM_001270448.2:c.1147C>T NP_001257377.1:p.Arg383Trp missense NC_000017.11:g.7224010C>T NC_000017.10:g.7127329C>T NG_007975.1:g.9177C>T NG_008391.2:g.1041G>A NG_033038.1:g.15535G>A P49748:p.Arg459Trp - Protein change
- R459W, R383W, R437W, R482W
- Other names
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- Canonical SPDI
- NC_000017.11:7224009:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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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ACADVL | - | - |
GRCh38 GRCh37 |
1725 | 1936 |
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
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 31, 2022 | RCV000506090.11 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 21, 2024 | RCV000652041.10 |
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
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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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Likely pathogenic
(Jan 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602370.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Nov 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV001364926.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1375C>T (NP_000009.1:p.Arg459Trp) [GRCH38: NC_000017.11:g.7224010C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported … (more)
The NM_000018.3:c.1375C>T (NP_000009.1:p.Arg459Trp) [GRCH38: NC_000017.11:g.7224010C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 (less)
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Uncertain significance
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500789.2
First in ClinVar: Apr 23, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: ACADVL c.1375C>T (p.Arg459Trp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Five … (more)
Variant summary: ACADVL c.1375C>T (p.Arg459Trp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1375C>T has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in heterozygous state. These reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely pathogenic
(Oct 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000773905.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 459 of the ACADVL protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 459 of the ACADVL protein (p.Arg459Trp). This variant is present in population databases (rs766742117, gnomAD 0.009%). This missense change has been observed in individual(s) with biochemical features of very long chain acyl-CoA dehydrogenase deficiency but in whom no second allele was reported (PMID: 9973285, 10738914, 21932095, 26385305; Invitae). ClinVar contains an entry for this variant (Variation ID: 203584). 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 ACADVL protein function. This variant disrupts the p.Arg459 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14517516, 19327992, 21429517, 23798014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
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Likely pathogenic
(Mar 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213666.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. | Miller MJ | Molecular genetics and metabolism | 2015 | PMID: 26385305 |
Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. | Waisbren SE | Developmental disabilities research reviews | 2013 | PMID: 23798014 |
VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. | Hoffmann L | Journal of inherited metabolic disease | 2012 | PMID: 21932095 |
Positive newborn screen in a normal infant of a mother with asymptomatic very long-chain Acyl-CoA dehydrogenase deficiency. | McGoey RR | The Journal of pediatrics | 2011 | PMID: 21429517 |
Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. | Laforêt P | Neuromuscular disorders : NMD | 2009 | PMID: 19327992 |
MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. | Spiekerkoetter U | The Journal of pediatrics | 2003 | PMID: 14517516 |
Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency. | Pons R | Pediatric neurology | 2000 | PMID: 10738914 |
Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. | Andresen BS | American journal of human genetics | 1999 | PMID: 9973285 |
Text-mined citations for rs766742117 ...
HelpRecord 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.