The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204)(PS3_Supporting). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knock-in Hs27 cells when compared to normal (PMID:32010688) (PS3_Supporting). This variant has been detected in at least 35 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, 34 of whom were homozygous for the variant (PMID: 28980192, 32010688, 10790204), and one compound heterozygous for a likely pathogenic without phase confirmation (PMID: 24801231)(PM3, Total points assigned = 1.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Multiple cases are observed with elevated C14:1 from NBS and reduced ACADVL activity, which is highly specific for VLCADD (PMID: 28980192,10790204)(PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified this variant as pathogenic based on PVS1,PS3_Supporting, PM3, PM2_Supporting, PP4_Moderate.
ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter)
Variation ID: 166638 Accession: VCV000166638.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7220124 (GRCh38) [ NCBI UCSC ] 17: 7123443 (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 Mar 24, 2015 Aug 25, 2024 Sep 22, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000018.4:c.65C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Ser22Ter nonsense NM_001033859.3:c.65C>A NP_001029031.1:p.Ser22Ter nonsense NM_001270447.2:c.134C>A NP_001257376.1:p.Ser45Ter nonsense NM_001270448.2:c.-164C>A 5 prime UTR NC_000017.11:g.7220124C>A NC_000017.10:g.7123443C>A NG_007975.1:g.5291C>A NG_008391.2:g.4927G>T - Protein change
- S22*, S45*
- Other names
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NM_000018.4(ACADVL):c.65C>A
p.Ser22Ter
- Canonical SPDI
- NC_000017.11:7220123:C: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
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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 |
1725 | 1937 | |
| LOC130060113 | - | - | - | GRCh38 | - | 90 |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2022 | RCV000152732.9 | |
| Pathogenic (9) |
reviewed by expert panel
|
Sep 22, 2022 | RCV000985184.15 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 22, 2022)
|
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
|
ClinGen ACADVL Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV002576798.2 First in ClinVar: Oct 08, 2022 Last updated: Apr 23, 2023 |
Comment:
The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated … (more)
The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204)(PS3_Supporting). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knock-in Hs27 cells when compared to normal (PMID:32010688) (PS3_Supporting). This variant has been detected in at least 35 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, 34 of whom were homozygous for the variant (PMID: 28980192, 32010688, 10790204), and one compound heterozygous for a likely pathogenic without phase confirmation (PMID: 24801231)(PM3, Total points assigned = 1.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Multiple cases are observed with elevated C14:1 from NBS and reduced ACADVL activity, which is highly specific for VLCADD (PMID: 28980192,10790204)(PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified this variant as pathogenic based on PVS1,PS3_Supporting, PM3, PM2_Supporting, PP4_Moderate. (less)
|
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Pathogenic
(Feb 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491231.3
First in ClinVar: Mar 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26182500, 24801231, 31130284, 32870709, 28980192, 10790204) (less)
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|
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Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV001364882.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.65C>A (NP_000009.1:p.Ser22Ter) [GRCH38: NC_000017.11:g.7220124C>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.65C>A (NP_000009.1:p.Ser22Ter) [GRCH38: NC_000017.11:g.7220124C>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:10790204. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 (less)
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Pathogenic
(Aug 01, 2020)
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criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001522466.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 10790204, 25525159, ClinVar … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 10790204, 25525159, ClinVar ID: 166638] (less)
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Pathogenic
(Mar 17, 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
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804750.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
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Pathogenic
(Mar 20, 2014)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226996.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 6
Sex: mixed
|
|
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Pathogenic
(Dec 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808516.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004297744.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 166638). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 166638). This premature translational stop signal has been observed in individuals with Very long-chain acyl-CoA dehydrogenase deficiency (PMID: 10790204, 32518924). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser22*) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). (less)
|
|
|
Pathogenic
(Dec 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005088800.2
First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024 |
Comment:
This variant is predicted to cause premature termination of the protein (p.Ser22Ter). The truncated protein is likely to lack catalytic domain and substrate binding region … (more)
This variant is predicted to cause premature termination of the protein (p.Ser22Ter). The truncated protein is likely to lack catalytic domain and substrate binding region of the protein [UniProt]; this will likely result in loss-of-function. The variant was previously reported in patients of Chinese and Israeli origin with very long chain acyl-CoA dehydrogenase deficiency in homozygous state [PMID: 26182500, 10790204]. (less)
|
|
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Pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133199.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV001438858.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Ethnicity/Population group: Arab
Geographic origin: Middle East
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Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26182500, 24801231, 31130284, 32870709, 28980192, 10790204)
Comment:
The NM_000018.3:c.65C>A (NP_000009.1:p.Ser22Ter) [GRCH38: NC_000017.11:g.7220124C>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:10790204. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 10790204, 25525159, ClinVar ID: 166638]
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 166638). This premature translational stop signal has been observed in individuals with Very long-chain acyl-CoA dehydrogenase deficiency (PMID: 10790204, 32518924). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser22*) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124).
Comment:
This variant is predicted to cause premature termination of the protein (p.Ser22Ter). The truncated protein is likely to lack catalytic domain and substrate binding region of the protein [UniProt]; this will likely result in loss-of-function. The variant was previously reported in patients of Chinese and Israeli origin with very long chain acyl-CoA dehydrogenase deficiency in homozygous state [PMID: 26182500, 10790204].
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. |
Comment:
The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204)(PS3_Supporting). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knock-in Hs27 cells when compared to normal (PMID:32010688) (PS3_Supporting). This variant has been detected in at least 35 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, 34 of whom were homozygous for the variant (PMID: 28980192, 32010688, 10790204), and one compound heterozygous for a likely pathogenic without phase confirmation (PMID: 24801231)(PM3, Total points assigned = 1.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Multiple cases are observed with elevated C14:1 from NBS and reduced ACADVL activity, which is highly specific for VLCADD (PMID: 28980192,10790204)(PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified this variant as pathogenic based on PVS1,PS3_Supporting, PM3, PM2_Supporting, PP4_Moderate.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26182500, 24801231, 31130284, 32870709, 28980192, 10790204)
Comment:
The NM_000018.3:c.65C>A (NP_000009.1:p.Ser22Ter) [GRCH38: NC_000017.11:g.7220124C>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:10790204. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 10790204, 25525159, ClinVar ID: 166638]
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 166638). This premature translational stop signal has been observed in individuals with Very long-chain acyl-CoA dehydrogenase deficiency (PMID: 10790204, 32518924). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser22*) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124).
Comment:
This variant is predicted to cause premature termination of the protein (p.Ser22Ter). The truncated protein is likely to lack catalytic domain and substrate binding region of the protein [UniProt]; this will likely result in loss-of-function. The variant was previously reported in patients of Chinese and Israeli origin with very long chain acyl-CoA dehydrogenase deficiency in homozygous state [PMID: 26182500, 10790204].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular and clinical characteristics of very-long-chain acyl-CoA dehydrogenase deficiency: A single-center experience in Saudi Arabia. | Alhashem A | Saudi medical journal | 2020 | PMID: 32518924 |
| 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 |
| Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse. | Cox KB | Human molecular genetics | 2001 | PMID: 11590124 |
| Molecular basis of very long chain acyl-CoA dehydrogenase deficiency in three Israeli patients: identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping. | Watanabe H | Human mutation | 2000 | PMID: 10790204 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a955db98-1e3b-463b-8b12-e2456a6ad0eb | - | - | - | - |
Text-mined citations for rs727503788 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.