VCV000235256.23 - ClinVar

NM_000018.4(ACADVL):c.1613G>C (p.Arg538Pro)

Germline

Classification

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000018.4(ACADVL):c.1613G>C (p.Arg538Pro)

Variation ID: 235256 Accession: VCV000235256.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7224487 (GRCh38) [ NCBI UCSC ] 17: 7127806 (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	Jun 9, 2016	Feb 14, 2024	Jun 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000018.4:c.1613G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000009.1:p.Arg538Pro	missense
NM_001033859.3:c.1547G>C	NP_001029031.1:p.Arg516Pro	missense
NM_001270447.2:c.1682G>C	NP_001257376.1:p.Arg561Pro	missense
NM_001270448.2:c.1385G>C	NP_001257377.1:p.Arg462Pro	missense
NC_000017.11:g.7224487G>C
NC_000017.10:g.7127806G>C
NG_007975.1:g.9654G>C
NG_008391.2:g.564C>G
NG_033038.1:g.15058C>G

... more HGVS ... less HGVS

Protein change

R538P, R516P, R561P, R462P

Other names

Canonical SPDI

NC_000017.11:7224486:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA8338191 dbSNP: rs201350598 VarSome

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
Gene	OMIM	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	1725	1936

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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 24, 2020	RCV000224776.4
Very long chain acyl-CoA dehydrogenase deficiency	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jun 9, 2023	RCV001200783.18

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 (Jan 30, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280696.2 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016
Pathogenic (Nov 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001364937.2 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020	Publications: PubMed (1) PubMed: 19327992 Comment: The NM_000018.3:c.1613G>C (NP_000009.1:p.Arg538Pro) [GRCH38: NC_000017.11:g.7224487G>C] 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.1613G>C (NP_000009.1:p.Arg538Pro) [GRCH38: NC_000017.11:g.7224487G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 19327992. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 (less)
Uncertain significance (Sep 24, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001803916.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter … (more) Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19327992, 27209629) (less)
Uncertain significance (May 11, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) 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: SCV002048084.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The ACADVL c.1613G>C; p.Arg538Pro variant (rs201350598) is reported in the literature in at least one individual affected with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency … (more) The ACADVL c.1613G>C; p.Arg538Pro variant (rs201350598) is reported in the literature in at least one individual affected with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (Laforet 2009). This variant is also reported in ClinVar (Variation ID: 235256), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 538 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.540). Due to the lack of clinical and functional data, the significance of the p.Arg538Pro variant is uncertain at this time. References: Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009 May;19(5):324-9. PMID: 19327992. (less)
Likely pathogenic (Jun 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002150346.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 19327992 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 235256). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 19327992). This variant is present in population databases (rs201350598, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 538 of the ACADVL protein (p.Arg538Pro). (less)
Uncertain significance (Aug 18, 2020)	no assertion criteria provided Method: clinical testing	Very long chain acyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088808.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

The NM_000018.3:c.1613G>C (NP_000009.1:p.Arg538Pro) [GRCH38: NC_000017.11:g.7224487G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 19327992. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

Comment:

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19327992, 27209629)

Comment:

The ACADVL c.1613G>C; p.Arg538Pro variant (rs201350598) is reported in the literature in at least one individual affected with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (Laforet 2009). This variant is also reported in ClinVar (Variation ID: 235256), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 538 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.540). Due to the lack of clinical and functional data, the significance of the p.Arg538Pro variant is uncertain at this time. References: Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009 May;19(5):324-9. PMID: 19327992.

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 235256). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 19327992). This variant is present in population databases (rs201350598, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 538 of the ACADVL protein (p.Arg538Pro).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency.	Laforêt P	Neuromuscular disorders : NMD	2009	PMID: 19327992

Text-mined citations for rs201350598 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000018.4(ACADVL):c.1613G>C (p.Arg538Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201350598 ...