ClinVar Genomic variation as it relates to human health
NM_014049.5(ACAD9):c.1237G>A (p.Glu413Lys)
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_014049.5(ACAD9):c.1237G>A (p.Glu413Lys)
Variation ID: 242463 Accession: VCV000242463.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.3 3: 128906208 (GRCh38) [ NCBI UCSC ] 3: 128625051 (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 Feb 18, 2019 Feb 14, 2024 Oct 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014049.5:c.1237G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054768.2:p.Glu413Lys missense NR_033426.2:n.1485G>A non-coding transcript variant NC_000003.12:g.128906208G>A NC_000003.11:g.128625051G>A NG_017064.1:g.31719G>A Q9H845:p.Glu413Lys - Protein change
- E413K
- Other names
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- Canonical SPDI
- NC_000003.12:128906207: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
Help
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
Help
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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ACAD9 | - | - |
GRCh38 GRCh37 |
771 | 1039 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2023 | RCV000756947.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2022 | RCV002282084.1 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2023 | RCV001782730.8 |
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
(Aug 04, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884941.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The c.1237G>A; p.Glu413Lys ACAD9 variant has been previously reported in a patient who also carried the c.187G>T; p.Glu62Ter variant. She presented after 4 months of … (more)
The c.1237G>A; p.Glu413Lys ACAD9 variant has been previously reported in a patient who also carried the c.187G>T; p.Glu62Ter variant. She presented after 4 months of age with feeding problems and poor weight gain, and at 5 months of age became acutely ill with a cough, breathlessness, pallor, anemia, moderate metabolic acidosis, and was diagnosed with encephalopathy and hypertrophic cardiomyopathy. Her cultured skin fibroblasts showed decreased complex I enzyme activity and no ACAD9 protein by SDS-PAGE analysis in fibroblasts. Her twin sister became acutely ill and progressed to organ failure with encephalopathy and hypertrophic cardiomyopathy as well (Nouws 2010). Nouws et al. (2010) showed by protein modeling that the replacement of glutamic acid by lysine in codon 413 will disturb the interaction with arginine 417, and will result in repulsion. The p.Glu413Lys ACAD9 variant was also reported in patient who also carried c.1552C>T; p.Arg518Cys variant and who first presented at four months of age with dyspnea, liver enlargement, elevated blood pressure, concentric hypertrophic cardiomyopathy, but at age 6 had only mildly elevated plasma and CSF lactate, ERG alteration and mild cardiac hypertrophy, and at age 22 had mild muscle weakness and dyspnea, but no other organ involvement or medication (Collet 2016). Schiff et al. (2015) showed no detectable dehydrogenase activity in the recombinant purified ACAD9 p.Glu413Lys mutant protein that was proven to be unstable. (less)
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Pathogenic
(Oct 26, 2023)
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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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Invitae
Accession: SCV000947158.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 413 of the ACAD9 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 413 of the ACAD9 protein (p.Glu413Lys). This variant is present in population databases (rs149753643, gnomAD 0.007%). This missense change has been observed in individuals with ACAD9 deficiency (PMID: 20816094, 26669660, 30025539, 30831263). ClinVar contains an entry for this variant (Variation ID: 242463). 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 ACAD9 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACAD9 function (PMID: 25721401). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex I deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571969.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: ACAD9 c.1237G>A (p.Glu413Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. … (more)
Variant summary: ACAD9 c.1237G>A (p.Glu413Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four 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 251400 control chromosomes (gnomAD). c.1237G>A has been reported in the literature in multiple individuals affected with Mitochondrial Complex I Deficiency (e.g. Nouws_2010, Schiff_2015, Repp_2018, Nogueira_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant had no detectable dehydrogenase activity (Schiff_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Acyl-CoA dehydrogenase 9 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV002761198.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
This variant was observed in compound heterozygosity with variant (c.1693-1G>A)
Clinical Features:
Abnormality of the cardiovascular system (present) , Respiratory distress (present)
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Pathogenic
(Jul 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Acyl-CoA dehydrogenase 9 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785757.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jun 30, 2023)
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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: SCV003936478.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
Reported previously in affected individuals who were heterozygous for the E413K variant and another ACAD9 variant (Nouws et al., 2010; Collet et al., 2016; Repp … (more)
Reported previously in affected individuals who were heterozygous for the E413K variant and another ACAD9 variant (Nouws et al., 2010; Collet et al., 2016; Repp et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In vitro studies show that variant may affect protein function (Schiff et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20816094, 30025539, 23996478, 30831263, 26669660, 31589614, 34426522, 32746448, 35314707, 25721401, 34646991) (less)
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Pathogenic
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Acyl-CoA dehydrogenase 9 deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209515.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Oct 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Acyl-CoA dehydrogenase 9 deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023969.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 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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Targeted next generation sequencing identifies novel pathogenic variants and provides molecular diagnoses in a cohort of pediatric and adult patients with unexplained mitochondrial dysfunction. | Nogueira C | Mitochondrion | 2019 | PMID: 30831263 |
Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? | Repp BM | Orphanet journal of rare diseases | 2018 | PMID: 30025539 |
High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood. | Collet M | European journal of human genetics : EJHG | 2016 | PMID: 26669660 |
Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. | Schiff M | Human molecular genetics | 2015 | PMID: 25721401 |
Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. | Nouws J | Cell metabolism | 2010 | PMID: 20816094 |
Text-mined citations for rs149753643 ...
HelpRecord last updated May 19, 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.