ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1878G>A (p.Trp626Ter)
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(2); Likely pathogenic(2); 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.1878G>A (p.Trp626Ter)
Variation ID: 541724 Accession: VCV000541724.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7225007 (GRCh38) [ NCBI UCSC ] 17: 7128326 (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 May 28, 2018 Jun 17, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1878G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Trp626Ter nonsense NM_001033859.3:c.1812G>A NP_001029031.1:p.Trp604Ter nonsense NM_001270447.2:c.1947G>A NP_001257376.1:p.Trp649Ter nonsense NM_001270448.2:c.1650G>A NP_001257377.1:p.Trp550Ter nonsense NC_000017.11:g.7225007G>A NC_000017.10:g.7128326G>A NG_007975.1:g.10174G>A NG_008391.2:g.44C>T NG_033038.1:g.14538C>T - Protein change
- W626*, W550*, W649*, W604*
- Other names
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- Canonical SPDI
- NC_000017.11:7225006:G:A
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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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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 |
1718 | 1926 |
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 (4) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV000652044.19 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2022 | RCV002293468.2 |
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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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: SCV001364944.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1878G>A (NP_000009.1:p.Trp626Ter) [GRCH38: NC_000017.11:g.7225007G>A] 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.1878G>A (NP_000009.1:p.Trp626Ter) [GRCH38: NC_000017.11:g.7225007G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 26385305. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 (less)
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Uncertain significance
(Aug 09, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883338.2
First in ClinVar: Feb 18, 2019 Last updated: Jan 26, 2021 |
Comment:
The ACADVL c.1878G>A; p.Trp626Ter variant is reported in the medical literature in at least one individual sent for newborn screening of very-long-chain acyl-CoA dehydrogenase deficiency … (more)
The ACADVL c.1878G>A; p.Trp626Ter variant is reported in the medical literature in at least one individual sent for newborn screening of very-long-chain acyl-CoA dehydrogenase deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 541724), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a premature termination codon and truncates the terminal 30 amino acids. These amino acids are unique amongst acyl-CoA dehydrogenases, but have no reported critical function (Goetzman 2007, McAndrew 2008). Due to limited information, the clinical significance of the p.Trp626Ter variant is uncertain at this time. References: Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. (less)
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Likely pathogenic
(Apr 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002586799.2
First in ClinVar: Oct 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Identified in an individual with a positive newborn screen for VLCAD deficiency (Miller et al., 2015); Nonsense variant in the C-terminus predicted to result in … (more)
Identified in an individual with a positive newborn screen for VLCAD deficiency (Miller et al., 2015); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26385305, 32778825) (less)
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Pathogenic
(May 08, 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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Invitae
Accession: SCV000773910.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Val642Met) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Val642Met) have been determined to be pathogenic (PMID: 31031081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 541724). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 32778825). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp626*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the ACADVL protein. (less)
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Likely pathogenic
(Mar 26, 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: SCV005053250.1
First in ClinVar: Jun 17, 2024 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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The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. | Rovelli V | Molecular genetics and metabolism | 2019 | PMID: 31031081 |
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 |
Text-mined citations for rs1555529186 ...
HelpRecord last updated Jun 17, 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.