ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)
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_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)
Variation ID: 92276 Accession: VCV000092276.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7224041 (GRCh38) [ NCBI UCSC ] 17: 7127360 (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 Mar 29, 2015 Feb 20, 2024 Oct 12, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1406G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Arg469Gln missense NM_001033859.3:c.1340G>A NP_001029031.1:p.Arg447Gln missense NM_001270447.2:c.1475G>A NP_001257376.1:p.Arg492Gln missense NM_001270448.2:c.1178G>A NP_001257377.1:p.Arg393Gln missense NC_000017.11:g.7224041G>A NC_000017.10:g.7127360G>A NG_007975.1:g.9208G>A NG_008391.2:g.1010C>T NG_033038.1:g.15504C>T P49748:p.Arg469Gln - Protein change
- R469Q, R393Q, R492Q, R447Q
- Other names
- NM_000018.4(ACADVL):c.1406G>A
- Canonical SPDI
- NC_000017.11:7224040: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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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 |
1703 | 1910 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (6) |
reviewed by expert panel
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Oct 12, 2022 | RCV000169627.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 6, 2012 | RCV000790745.12 |
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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Likely pathogenic
(Oct 12, 2022)
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reviewed by expert panel
Method: curation
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Very long chain acyl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ACADVL Variant Curation Expert Panel, ClinGen
Accession: SCV002769758.2
First in ClinVar: Dec 31, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has … (more)
The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency; of the 3 homozygous individuals, 2 were monozygotic twins; in one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID: 25834949). Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM5, PM1, PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-16-2022). (less)
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Pathogenic
(Aug 06, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225985.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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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: SCV001364931.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1406G>A (NP_000009.1:p.Arg469Gln) [GRCH38: NC_000017.11:g.7224041G>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.1406G>A (NP_000009.1:p.Arg469Gln) [GRCH38: NC_000017.11:g.7224041G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 (less)
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Likely pathogenic
(Feb 25, 2015)
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criteria provided, single submitter
Method: literature only
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Very long chain acyl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221156.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 15, 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:
unknown
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Baylor Genetics
Accession: SCV004211910.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 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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Invitae
Accession: SCV001413446.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 469 of the ACADVL protein (p.Arg469Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 469 of the ACADVL protein (p.Arg469Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 25834949). This variant is also known as R429Q. ClinVar contains an entry for this variant (Variation ID: 92276). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg469 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9973285, 17374501, 17999356, 27246109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 31, 2020)
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no assertion criteria provided
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002088796.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. | Evans M | Molecular genetics and metabolism | 2016 | PMID: 27246109 |
Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency. | Diekman EF | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25834949 |
Muscle MRI in patients with long-chain fatty acid oxidation disorders. | Diekman EF | Journal of inherited metabolic disease | 2014 | PMID: 24305961 |
Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. | Waisbren SE | Developmental disabilities research reviews | 2013 | PMID: 23798014 |
Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. | Gobin-Limballe S | American journal of human genetics | 2007 | PMID: 17999356 |
Very long chain acyl-CoA dehydrogenase deficiency in a pair of mildly affected monozygotic twin sister in their late fifties. | Zia A | Journal of inherited metabolic disease | 2007 | PMID: 17514507 |
Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. | Goetzman ES | Molecular genetics and metabolism | 2007 | PMID: 17374501 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6e8b7ddb-d3d0-4774-8cd9-f8c0a79307dd | - | - | - | - |
Text-mined citations for rs398123083 ...
HelpRecord last updated Mar 23, 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.