ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1349G>A (p.Arg450His)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000018.4(ACADVL):c.1349G>A (p.Arg450His)
Variation ID: 1634 Accession: VCV000001634.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7223984 (GRCh38) [ NCBI UCSC ] 17: 7127303 (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 25, 2017 Jun 17, 2024 Dec 14, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1349G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Arg450His missense NM_000018.2:c.1349G>A NM_001033859.3:c.1283G>A NP_001029031.1:p.Arg428His missense NM_001270447.1:c.1418G>A NM_001270447.2:c.1418G>A NP_001257376.1:p.Arg473His missense NM_001270448.2:c.1121G>A NP_001257377.1:p.Arg374His missense NC_000017.11:g.7223984G>A NC_000017.10:g.7127303G>A NG_007975.1:g.9151G>A NG_008391.2:g.1067C>T NG_033038.1:g.15561C>T P49748:p.Arg450His - Protein change
- R450H, R374H, R428H, R473H
- Other names
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R410H
NM_000018.4(ACADVL):c.1349G>A
- Canonical SPDI
- NC_000017.11:7223983: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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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
- 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
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 |
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
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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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Likely pathogenic (10) |
reviewed by expert panel
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Dec 14, 2022 | RCV000001701.23 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003625.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2019 | RCV000724571.13 |
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
(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: SCV002769745.2 First in ClinVar: Dec 31, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one … (more)
The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one individual with this variant displayed reduced VLCAD activity, which is specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 11158518). This variant has been confirmed in trans to at least one likely pathogenic variant, not confirmed in trans to distinct likely pathogenic variants, and has been identified in the homozygous state in 2 individuals (PM3_Strong, PMID: 29519241, 15210884, 11158518, 9546340). The highest population minor allele frequency in gnomAD v2.0 is 0.00025 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) (less)
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Pathogenic
(Jul 19, 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: SCV001811368.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 31130284, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 31130284, 30840296, 11158518, 20060901, 24801231, 29519241, 28980192, 29552494, 27246109, 25652019, 9973285, 9546340, 15210884) (less)
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Likely pathogenic
(Jan 27, 2015)
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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: SCV000225986.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Apr 23, 2018)
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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: SCV000884952.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
The ACADVL c.1349G>A; p.Arg450His variant (rs118204016), also known as Arg410His for traditional nomenclature, is reported multiple times in the literature in association with VLCAD deficiency … (more)
The ACADVL c.1349G>A; p.Arg450His variant (rs118204016), also known as Arg410His for traditional nomenclature, is reported multiple times in the literature in association with VLCAD deficiency and is reported both in the homozygous and compound heterozygous states in affected individuals (Andresen 1999, Fukao 2001, Gobin-Limballe 2010, Kang 2018, Ohashi 2004, Smelt 1998, Zhang 2014). Additionally, functional analyses of the variant protein show decreased expression and enzymatic activity (Fukao 2001, Smelt 1998). This variant is reported in ClinVar (Variation ID: 1634) and found in the general population with a low overall allele frequency of 0.003% (8/277108 alleles) in the Genome Aggregation Database. The arginine at codon 450 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Fukao T et al. Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl. Pediatr Res. 2001 Feb;49(2):227-31. 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 May;1802(5):478-84. Kang E et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018 Mar 8;18(1):103. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. Smelt AH et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998 Apr;43(4):540-4. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25. (less)
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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: SCV001364921.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1349G>A (NP_000009.1:p.Arg450His) [GRCH38: NC_000017.11:g.7223984G>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.1349G>A (NP_000009.1:p.Arg450His) [GRCH38: NC_000017.11:g.7223984G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 (less)
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Pathogenic
(May 09, 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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Revvity Omics, Revvity
Accession: SCV004235433.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 07, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241874.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: ACADVL c.1349G>A (p.Arg450His) 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.1349G>A (p.Arg450His) 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 2.4e-05 in 251342 control chromosomes (gnomAD). c.1349G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Fukao_2001, Osawa_2022), and some were compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Fukao_2001). Seven submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 10, 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: SCV000654930.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACADVL protein (p.Arg450His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACADVL protein (p.Arg450His). This variant is present in population databases (rs118204016, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9546340, 11158518, 15210884, 24801231). This variant is also known as R410H. ClinVar contains an entry for this variant (Variation ID: 1634). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 11158518). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 14, 2024)
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criteria provided, single submitter
Method: research
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801148.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
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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
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847467.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg473His variant in ACADVL has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state in at … (more)
The p.Arg473His variant in ACADVL has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state in at least 7 individuals with very long chain acyl-CoA dehydrogenase deficiency, at least one of whom showed reduced enzyme activity consistent with the condition. In at least 4 of these individuals, the p.Arg473His was identified with a potentially disease causing variant in ACADVL, and the variants were confirmed to be in trans in at least 1 individual (Andresen 1999 PMID: 9973285, Fukao 2001 PMID: 11158518, Smelt 1998 PMID: 9546340, Ohashi 2004 PMID: 15210884, Osawa 2022 PMID: 35400565). This variant has also been identified in 0.01% (6/44888) of East Asian chromosomes by gnomAD, including 1 homozygote in the South Asian population (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies of enzymatic activity and protein expression provide some evidence that this variant impacts protein function (Fukao 2001 PMID: 11158518; Ohashi 2004 PMID: 15210884; Osawa 2022 PMID: 35400565) and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as likely pathogenic on Dec 14, 2022 by the ClinGen-approved ACADVL Variant Curation Expert Panel (Variation ID 1634). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PP4, PP3, PM2_Supporting. (less)
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Pathogenic
(Feb 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: SCV004210767.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 01, 2001)
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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: SCV000021857.3
First in ClinVar: Apr 04, 2013 Last updated: May 25, 2017 |
Comment on evidence:
For discussion of the arg450-to-his (R450H) substitution in the ACADVL gene that was found in compound heterozygous state in a Japanese patient with VLCAD deficiency … (more)
For discussion of the arg450-to-his (R450H) substitution in the ACADVL gene that was found in compound heterozygous state in a Japanese patient with VLCAD deficiency by Fukao et al. (2001), see 609575.0013. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Abnormal circulating enzyme concentration
Rhabdomyolysis
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162036.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
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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: SCV001459255.1
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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The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening. | Osawa Y | Molecular genetics and metabolism | 2022 | PMID: 35400565 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. | Zhang RN | World journal of pediatrics : WJP | 2014 | PMID: 24801231 |
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 |
A new diagnostic test for VLCAD deficiency using immunohistochemistry. | Ohashi Y | Neurology | 2004 | PMID: 15210884 |
Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl. | Fukao T | Pediatric research | 2001 | PMID: 11158518 |
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 |
Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. | Smelt AH | Annals of neurology | 1998 | PMID: 9546340 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ab1b756a-f061-4e35-bdc2-4d326b69f79d | - | - | - | - |
Text-mined citations for rs118204016 ...
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.