ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.652G>A (p.Glu218Lys)
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.652G>A (p.Glu218Lys)
Variation ID: 474901 Accession: VCV000474901.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7221981 (GRCh38) [ NCBI UCSC ] 17: 7125300 (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 10, 2018 Feb 20, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000018.4:c.652G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Glu218Lys missense NM_001033859.3:c.586G>A NP_001029031.1:p.Glu196Lys missense NM_001270447.2:c.721G>A NP_001257376.1:p.Glu241Lys missense NM_001270448.2:c.424G>A NP_001257377.1:p.Glu142Lys missense NC_000017.11:g.7221981G>A NC_000017.10:g.7125300G>A NG_007975.1:g.7148G>A NG_008391.2:g.3070C>T - Protein change
- E218K, E142K, E196K, E241K
- Other names
- NM_000018.4(ACADVL):c.652G>A
- p.Glu218Lys
- Canonical SPDI
- NC_000017.11:7221980:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ACADVL | - | - |
GRCh38 GRCh37 |
1708 | 1913 |
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 (5) |
reviewed by expert panel
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Nov 28, 2023 | RCV000556767.16 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Nov 28, 2023)
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reviewed by expert panel
Method: curation
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Very long chain acyl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ACADVL Variant Curation Expert Panel, ClinGen
Accession: SCV002769772.3
First in ClinVar: Dec 31, 2022 Last updated: Dec 24, 2023 |
Comment:
The c.652G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 218 (p.Glu218Lys, also … (more)
The c.652G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 218 (p.Glu218Lys, also known as Glu178Lys in traditional nomenclature). At least two patients with this variant displayed elevated C14:1 by newborn screen and/or reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 34184355, 30194637). Of those individuals, one was homozygous for the variant, confirmed by parental testing, and one was presumed in trans to a pathogenic variant (PM3 1 point; PMIDs: 34184355, 30194637). Additionally, one patient carrying this variant displayed a reduced VLCAD protein level (PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000032 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.957, 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: PM1, PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 15, 2022 and the recurated classification was approved by the expert panel on November 13, 2023. (less)
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Likely pathogenic
(Oct 16, 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: SCV002780521.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 11, 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: SCV003800885.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: ACADVL c.652G>A (p.Glu218Lys) results in a conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. … (more)
Variant summary: ACADVL c.652G>A (p.Glu218Lys) results in a conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 4e-06 in 251352 control chromosomes. c.652G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) (example, Andresen_1999, Hesse_2018, Takizaki_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 2% of normal VLCAD enzyme activity in leukocytes from a homozygous individual affected with VLCAD deficiency. Two clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=2; VUS, n=1). The expert panel classification as a VUS has cited overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210789.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 29, 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: SCV000654961.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 218 of the ACADVL protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 218 of the ACADVL protein (p.Glu218Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl co-A dehydrogenase deficiency (PMID: 9973285, 30194637; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Glu178Lys. ClinVar contains an entry for this variant (Variation ID: 474901). 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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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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Very long-chain acyl-CoA dehydrogenase deficiency: No developmental delay after cardiopulmonary arrest. | Takizaki N | Pediatrics international : official journal of the Japan Pediatric Society | 2021 | PMID: 34184355 |
The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). | Hesse J | Journal of inherited metabolic disease | 2018 | PMID: 30194637 |
Novel mutations in the gene encoding very long-chain acyl-CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase II deficiency. | Isackson PJ | Muscle & nerve | 2013 | PMID: 23169530 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4eb52b3c-3d84-48d6-a3cb-9a64c6d1cb74 | - | - | - | - |
Text-mined citations for rs1432183079 ...
HelpRecord last updated Feb 20, 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.