ClinVar Genomic variation as it relates to human health
NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)
Variation ID: 92270 Accession: VCV000092270.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7222789 (GRCh38) [ NCBI UCSC ] 17: 7126108 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 29, 2016 Feb 14, 2024 Dec 6, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000018.4:c.1001T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000009.1:p.Met334Arg missense NM_001033859.3:c.935T>G NP_001029031.1:p.Met312Arg missense NM_001270447.2:c.1070T>G NP_001257376.1:p.Met357Arg missense NM_001270448.2:c.773T>G NP_001257377.1:p.Met258Arg missense NC_000017.11:g.7222789T>G NC_000017.10:g.7126108T>G NG_007975.1:g.7956T>G NG_008391.2:g.2262A>C - Protein change
- M334R, M312R, M258R, M357R
- Other names
- p.M334R:ATG>AGG
- Canonical SPDI
- NC_000017.11:7222788:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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. |
|||
ACADVL | - | - |
GRCh38 GRCh37 |
1704 | 1909 |
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. |
---|---|---|---|---|
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 24, 2021 | RCV000077898.23 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Dec 6, 2023 | RCV000668860.32 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 21, 2020 | RCV001174775.9 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Oct 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060163.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000018.3(ACADVL):c.1001T>G(M334R) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. M334R has been observed in … (more)
NM_000018.3(ACADVL):c.1001T>G(M334R) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. M334R has been observed in cases with relevant disease (PMID: 27209629). Functional assessments of this variant are not available in the literature. M334R has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1001T>G(M334R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
Uncertain significance
(Apr 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160513.3
First in ClinVar: Feb 10, 2020 Last updated: Mar 04, 2023 |
Comment:
The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena … (more)
The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena 2016). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 92270), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 334 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, given the lack of clinical and functional data, the significance of the p.Met334Arg variant is uncertain at this time. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. 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. PMID: 27209629. (less)
|
|
Likely pathogenic
(Jul 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215114.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Aug 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003822472.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Very long chain acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000815383.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the ACADVL protein (p.Met334Arg). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the ACADVL protein (p.Met334Arg). This variant is present in population databases (rs398123079, gnomAD 0.004%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 27209629; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92270). 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)
|
|
Uncertain Significance
(Feb 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280923.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Converted during submission to Uncertain significance.
|
|
Uncertain significance
(Jul 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000109727.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Uncertain significance
(Jan 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338104.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ACADVL c.1001T>G (p.Met334Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Five … (more)
Variant summary: ACADVL c.1001T>G (p.Met334Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain 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 1.6e-05 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1001T>G has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency following newborn screening results (Miller_2015, Pena_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Likely 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: SCV001365225.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The NM_000018.3:c.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
The NM_000018.3:c.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3 (less)
|
|
Uncertain significance
(Sep 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238642.15
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple individuals with an abnormal newborn screening result for VLCAD deficiency in whom a second ACADVL variant was not identified (Miller et al. … (more)
Reported in multiple individuals with an abnormal newborn screening result for VLCAD deficiency in whom a second ACADVL variant was not identified (Miller et al. 2015); Reported in an asymptomatic individual diagnosed with VLCAD deficiency via molecular testing and acylcarnitine profile analysis following an abnormal newborn screening result. This individual also had a second missense variant identified in the ACADVL gene although the phase of the two variants was not reported (Pena et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 27209629, 26385305) (less)
|
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 |
---|---|---|---|---|
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 |
Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. | Miller MJ | Molecular genetics and metabolism | 2015 | PMID: 26385305 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADVL | - | - | - | - |
Text-mined citations for rs398123079 ...
HelpRecord last updated Apr 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.