ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1322G>A (p.Gly441Asp)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000018.4(ACADVL):c.1322G>A (p.Gly441Asp)
Variation ID: 21016 Accession: VCV000021016.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7223865 (GRCh38) [ NCBI UCSC ] 17: 7127184 (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 4, 2013 Jun 17, 2024 Dec 14, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1322G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Gly441Asp missense NM_001033859.3:c.1256G>A NP_001029031.1:p.Gly419Asp missense NM_001270447.2:c.1391G>A NP_001257376.1:p.Gly464Asp missense NM_001270448.2:c.1094G>A NP_001257377.1:p.Gly365Asp missense NC_000017.11:g.7223865G>A NC_000017.10:g.7127184G>A NG_007975.1:g.9032G>A NG_008391.2:g.1186C>T NG_033038.1:g.15680C>T P49748:p.Gly441Asp - Protein change
- G441D, G365D, G464D, G419D
- Other names
- G401D
- NM_000018.4(ACADVL):c.1322G>A
- Canonical SPDI
- NC_000017.11:7223864: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.
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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
Help
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
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
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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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Pathogenic (12) |
reviewed by expert panel
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Dec 14, 2022 | RCV000020072.40 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 13, 2021 | RCV000077903.25 |
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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Pathogenic
(Dec 14, 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
FDA Recognized Database
Accession: SCV002769744.2 First in ClinVar: Dec 31, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least … (more)
The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least two individuals with this variant displayed VLCAD enzyme activity <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 25834949). The variant has been described in the homozygous state in at least 4 affected individuals, confirmed in trans to a pathogenic variant in at least one individual, and in at least one individual with a distinct pathogenic variant without determination of phase of the variants (PM3_Strong; PMIDs: 1648817, 17999356, 24305961, 30194637, 32061778). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion. This variant occurs adjacent to the FAD binding pocket and is located on a loop that contributes to dimer formation (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.982, 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) (less)
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Pathogenic
(Nov 18, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280823.2
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(May 03, 2013)
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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: SCV000225740.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 7
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: SCV001364920.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1322G>A (NP_000009.1:p.Gly441Asp) [GRCH38: NC_000017.11:g.7223865G>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.1322G>A (NP_000009.1:p.Gly441Asp) [GRCH38: NC_000017.11:g.7223865G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17999356. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 (less)
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Pathogenic
(May 28, 2020)
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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: SCV000602359.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
Comment:
The ACADVL p.Gly441Asp variant has been described in the literature in individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and fibroblasts from at least … (more)
The ACADVL p.Gly441Asp variant has been described in the literature in individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and fibroblasts from at least one of these individuals have been shown to have reduced function (Andresen 1996, Gobin-Limballe 2010). The variant is listed in the dbSNP variant database (rs2309689) with an allele frequency 0.0008242 percent in the Exome Aggregation Consortium. The glycine at codon 441 is well conserved across species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Taken together, this variant is considered pathogenic. REFERENCES Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996; 5(4):461-72. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010; 1802(5):478-84. (less)
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Pathogenic
(Nov 13, 2019)
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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: SCV001824991.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8845838, 25525159, 16288870, 16443431, 31031081, 20060901, 17999356, 23867825, 16488171, 9546340, 26453363, 23757202, 27246109, 11158518, 20301763, 21378393) (less)
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Pathogenic
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002499701.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1
Number of individuals with the variant: 1
Clinical Features:
Decreased 3-hydroxyacyl-CoA dehydrogenase level (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(Apr 13, 2021)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002525837.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
PS3, PS4, PM2, PM3, PP4
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Pathogenic
(Feb 13, 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: SCV004210845.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jun 04, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361318.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ACADVL c.1322G>A (p.Gly441Asp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. … (more)
Variant summary: ACADVL c.1322G>A (p.Gly441Asp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) 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 2.8e-05 in 251362 control chromosomes (gnomAD). c.1322G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Diekman_2015, Miller_2015, Gobin-Limballe_2010, Andresen_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated fibroblast cells derived from VLCAD patients carrying p.Gly441Asp to have considerably reduced enzyme activity and long-chain fatty acid-oxidation flux compared to controls (Diekman_2015, Gobin-Limballe_2010, Andresen_1996). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Sep 05, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810408.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 22, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003808449.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 04, 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:
germline
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Invitae
Accession: SCV000654927.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 441 of the ACADVL protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 441 of the ACADVL protein (p.Gly441Asp). This variant is present in population databases (rs2309689, gnomAD 0.005%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 8845838, 16443431, 17999356, 24305961). ClinVar contains an entry for this variant (Variation ID: 21016). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 1998)
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no assertion criteria provided
Method: literature only
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VLCAD DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021852.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In a 42-year-old woman with late-onset VLCAD deficiency (201475), Smelt et al. (1998) identified compound heterozygosity for 2 mutations in the ACADVL gene: a G-to-A … (more)
In a 42-year-old woman with late-onset VLCAD deficiency (201475), Smelt et al. (1998) identified compound heterozygosity for 2 mutations in the ACADVL gene: a G-to-A transition in exon 13, resulting in a gly401-to-asp (G401D) substitution, and a G-to-A transition in exon 14, resulting in an arg410-to-his (R410H; 609575.0010) substitution. The patient had recurrent rhabdomyolysis and markedly elevated levels of tetradecadienoic acid and hexadecadienoic acid. (less)
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Pathogenic
(May 04, 2018)
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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:
unknown
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Counsyl
Accession: SCV000486487.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 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: SCV001459254.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Prediction of VLCAD deficiency phenotype by a metabolic fingerprint in newborn screening bloodspots. | Knottnerus SJG | Biochimica et biophysica acta. Molecular basis of disease | 2020 | PMID: 32061778 |
Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. | Rovelli V | Molecular genetics and metabolism | 2019 | PMID: 31031081 |
The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). | Hesse J | Journal of inherited metabolic disease | 2018 | PMID: 30194637 |
VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. | Evans M | Molecular genetics and metabolism | 2016 | PMID: 27246109 |
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 |
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 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Muscle MRI in patients with long-chain fatty acid oxidation disorders. | Diekman EF | Journal of inherited metabolic disease | 2014 | PMID: 24305961 |
Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. | Gobin-Limballe S | Biochimica et biophysica acta | 2010 | PMID: 20060901 |
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 |
VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. | Boneh A | Molecular genetics and metabolism | 2006 | PMID: 16488171 |
Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. | Voermans NC | The American journal of medicine | 2006 | PMID: 16443431 |
Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. | Mathur A | Circulation | 1999 | PMID: 10077518 |
Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. | Smelt AH | Annals of neurology | 1998 | PMID: 9546340 |
Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. | Andresen BS | Human molecular genetics | 1996 | PMID: 8845838 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7632a574-ebef-41ce-8cb8-6a5028bf2de6 | - | - | - | - |
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Text-mined citations for rs2309689 ...
HelpRecord last updated Sep 08, 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.