ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1844G>A (p.Arg615Gln)
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.1844G>A (p.Arg615Gln)
Variation ID: 195448 Accession: VCV000195448.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7224973 (GRCh38) [ NCBI UCSC ] 17: 7128292 (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 Oct 5, 2015 Apr 15, 2024 Jun 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.1844G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Arg615Gln missense NM_001033859.3:c.1778G>A NP_001029031.1:p.Arg593Gln missense NM_001270447.2:c.1913G>A NP_001257376.1:p.Arg638Gln missense NM_001270448.2:c.1616G>A NP_001257377.1:p.Arg539Gln missense NC_000017.11:g.7224973G>A NC_000017.10:g.7128292G>A NG_007975.1:g.10140G>A NG_008391.2:g.78C>T NG_033038.1:g.14572C>T P49748:p.Arg615Gln - Protein change
- R615Q, R539Q, R593Q, R638Q
- Other names
- p.R615Q:CGA>CAA
- NM_000018.4(ACADVL):c.1844G>A
- Canonical SPDI
- NC_000017.11:7224972: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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
The Genome Aggregation Database (gnomAD) 0.00244
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00254
Trans-Omics for Precision Medicine (TOPMed) 0.00271
Exome Aggregation Consortium (ExAC) 0.00285
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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ACADVL | - | - |
GRCh38 GRCh37 |
1707 | 1912 |
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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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000176020.39 | |
Likely benign (10) |
reviewed by expert panel
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Jun 27, 2023 | RCV000193309.39 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 10, 2022 | RCV002307434.2 |
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
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 benign
(Jun 27, 2023)
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reviewed by expert panel
Method: curation
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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ClinGen ACADVL Variant Curation Expert Panel, ClinGen
Accession: SCV003936886.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The c.1844G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 615 (p.Arg615Gln), also called Arg575Gln … (more)
The c.1844G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 615 (p.Arg615Gln), also called Arg575Gln in the processed peptide. The variant has been identified in individuals identified by positive newborn screen, or identified in individuals with suspected very long chain acyl-CoA dehydrogenase (VLCAD) deficiency that was not confirmed biochemically, but this information is insufficient to use toward classification (PMID: 10077518, 17999356, 27209629, 21932095, 26453363). The variant has been reported to occur in individuals who also carried a distinct ACADVL variant not confirmed in trans; however, since none of these individuals met PP4, the ACADVL VCEP could not count these toward PM3 evidence (PMID: 17999356, 21932095, 27209629). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.003654 in the European (non-Finnish) population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.0035) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.397, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4 (ACADVL VCEP specifications version 1; approved November 8, 2021). (less)
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Uncertain significance
(Apr 05, 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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Eurofins Ntd Llc (ga)
Accession: SCV000227603.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001282893.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(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: SCV001365217.2
First in ClinVar: Jul 11, 2020 Last updated: Jul 11, 2020 |
Comment:
The NM_000018.3:c.1844G>A (NP_000009.1:p.Arg615Gln) [GRCH38: NC_000017.11:g.7224973G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
The NM_000018.3:c.1844G>A (NP_000009.1:p.Arg615Gln) [GRCH38: NC_000017.11:g.7224973G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4 (less)
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Uncertain significance
(May 18, 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: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001737187.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
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Uncertain significance
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600383.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: ACADVL c.1844G>A (p.Arg615Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: ACADVL c.1844G>A (p.Arg615Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251176 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. An additional 5 homozygous occurrences have been reported in the literature in individuals with lack of phenotype (Abouelhoda_2016, Kars_2021). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) phenotype (0.0029), suggesting that the variant is a benign polymorphism. c.1844G>A has been reported in the literature as a biallelic genotype in individuals with mild forms of VLCAD deficiency and in individuals identified through Newborn Screening who were asymptomatic (e.g. Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016, Pena_2016). Residual enzymatic activities in compound heterozygous individuals carrying pathogenic variants in trans ranged from 21%, to 40% and up to similar activity to controls (Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016). In one simple heterozygous individual with the variant, residual enzymatic activity was measured at 39% (Hoffmann_2012), with the authors concluding from their study that individuals with a residual enzyme activity >20% present with a biochemical phenotype but likely remain asymptomatic throughout life. The variant was found to co-occur in cis with a pathogenic variant in one homozygous and one compound heterozygous individuals who had symptoms of VLCAD (Merinero_2018). Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, and four as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Likely benign
(-)
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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: SCV001163428.3
First in ClinVar: Feb 28, 2020 Last updated: Mar 18, 2023 |
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Uncertain significance
(Apr 27, 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: SCV000238661.15
First in ClinVar: Jul 18, 2015 Last updated: Jun 17, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28755359, 27884173, 21932095, 27209629, 10077518, 17999356, 30194637, 26453363, 34485012, 32778825, 34426522, 35281663, 35626289) (less)
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Uncertain significance
(Feb 23, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782653.2
First in ClinVar: Jul 07, 2018 Last updated: Jan 26, 2024 |
Comment:
BS1
Number of individuals with the variant: 3
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Likely benign
(Jan 31, 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: SCV000654946.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Nov 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602356.5
First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024 |
Comment:
The ACADVL p.Arg615Gln variant (rs148584617; ClinVar variation ID: 195448) has been previously identified by our laboratory, and is described in the literature in multiple patients … (more)
The ACADVL p.Arg615Gln variant (rs148584617; ClinVar variation ID: 195448) has been previously identified by our laboratory, and is described in the literature in multiple patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Mathur 1999, Hoffmann 2012, Diekman 2016, Pena 2016). However the exact contribution of this variant to the clinical presentation of these patients is unclear. The enzyme activity in cells isolated from patients with VCLAD was reported to range from 21% of control activity (Hoffmann 2012) to 40% (Diekman 2016) to be indistinguishable from control activity (Gobin-Limballe 2007) for p.Arg615Gln when in trans with different ACADVL variants. And at least one study identified this variant in two individuals who failed newborn screening, but had not developed symptoms at age 2 (Diekman 2016). Furthermore, this variant is found in the general population with an overall allele frequency of 0.27% (758/282,554 alleles, including 4 homozygotes) in the Genome Aggregation Database. The arginine at codon 615 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.397). Due to conflicting information, the clinical significance of the p.Arg615Gln variant is uncertain at this time. References: Diekman E et al. The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. JIMD Rep. 2016;27:101-6. PMID: 26453363. Gobin-Limballe et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6): 1133-1143. PMID: 17999356. Hoffmann et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2): 269-277. PMID: 21932095. Mathur et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10): 1337-1343. PMID: 10077518. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PubMed: 27209629. Tabor et al. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Am J Hum Genet. 2014; 95(2): 183-193. PubMed: 25087612. (less)
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Likely benign
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780557.23
First in ClinVar: Dec 06, 2016 Last updated: Apr 15, 2024 |
Comment:
ACADVL: BP4, BS2
Number of individuals with the variant: 5
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Likely benign
(Jan 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: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440708.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
|
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Likely benign
(Jun 19, 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
|
Natera, Inc.
Accession: SCV001455191.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799068.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932461.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958927.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973985.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Oct 13, 2014)
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no assertion criteria provided
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV000223917.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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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 Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. | Sepp R | Diagnostics (Basel, Switzerland) | 2022 | PMID: 35626289 |
Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region. | Martín-Rivada Á | JIMD reports | 2022 | PMID: 35281663 |
Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity. | Hagemeijer MC | JIMD reports | 2021 | PMID: 34485012 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). | Hesse J | Journal of inherited metabolic disease | 2018 | PMID: 30194637 |
Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. | Merinero B | JIMD reports | 2018 | PMID: 28755359 |
Revisiting the morbid genome of Mendelian disorders. | Abouelhoda M | Genome biology | 2016 | PMID: 27884173 |
Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. | Pena LD | Molecular genetics and metabolism | 2016 | PMID: 27209629 |
The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. | Diekman E | JIMD reports | 2016 | PMID: 26453363 |
VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. | Hoffmann L | Journal of inherited metabolic disease | 2012 | PMID: 21932095 |
Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts. | Bastin J | Human molecular genetics | 2011 | PMID: 21378393 |
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 |
Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. | Mathur A | Circulation | 1999 | PMID: 10077518 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/303ae949-d48d-4735-a7b0-38184eac3d4e | - | - | - | - |
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Text-mined citations for rs148584617 ...
HelpRecord last updated Apr 15, 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.