VCV000623120.24 - ClinVar

NM_000017.4(ACADS):c.596C>T (p.Ala199Val)

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.

(7)

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.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000017.4(ACADS):c.596C>T (p.Ala199Val)

Variation ID: 623120 Accession: VCV000623120.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.31 12: 120737960 (GRCh38) [ NCBI UCSC ] 12: 121175763 (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	Mar 25, 2019	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000017.4:c.596C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000008.1:p.Ala199Val	missense
NM_001302554.2:c.473-89C>T		intron variant
NC_000012.12:g.120737960C>T
NC_000012.11:g.121175763C>T
NG_007991.1:g.17193C>T

... more HGVS ... less HGVS

Protein change

A199V

Other names

Canonical SPDI

NC_000012.12:120737959:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

dbSNP: rs766579880 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.
ACADS		-	-	GRCh38 GRCh37	444	463

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.
Deficiency of butyryl-CoA dehydrogenase	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 30, 2023	RCV000761220.14
not provided	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV001551168.11
ACADS-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV003413549.4

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.
Likely pathogenic (Dec 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000891174.1 First in ClinVar: Mar 25, 2019 Last updated: Mar 25, 2019	Publications: PubMed (1) PubMed: 185223805 Number of individuals with the variant: 1
Likely pathogenic (Jul 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001771617.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021	Comment: Reported in association with SCAD deficiency in individuals with failure to thrive, feeding difficulties and hypotonia who were compound heterozygous for the G209S variant (Pedersen … (more) Reported in association with SCAD deficiency in individuals with failure to thrive, feeding difficulties and hypotonia who were compound heterozygous for the G209S variant (Pedersen et al., 2008); In vitro functional studies demonstrated A199V had a damaging effect on SCAD protein. Functional studies with complex allele including A199V and G209S caused a severe effect (Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 28263315, 18523805) (less)
Likely pathogenic (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002033245.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely pathogenic (Jul 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ACADS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114524.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ACADS c.596C>T variant is predicted to result in the amino acid substitution p.Ala199Val. This variant has been reported in patients with short chain acyl-coA … (more) The ACADS c.596C>T variant is predicted to result in the amino acid substitution p.Ala199Val. This variant has been reported in patients with short chain acyl-coA dehydrogenase (SCAD) deficiency (Pedersen et al. 2008. PubMed ID: 18523805; Long et al. 2017. PubMed ID: 28263315). In experimental studies, the p.Ala199Val variant was shown to lead to defective tetramer formation and increased protein aggregation (Pedersen et al. 2008. PubMed ID: 18523805). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-121175763-C-T). This variant is interpreted as likely pathogenic. (less)
Likely pathogenic (Jun 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of butyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000960558.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 18523805‚ 28263315 Comment: This variant is present in population databases (rs766579880, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral … (more) This variant is present in population databases (rs766579880, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 199 of the ACADS protein (p.Ala199Val). This missense change has been observed in individuals with clinical features of short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18523805, 28263315; Invitae). ClinVar contains an entry for this variant (Variation ID: 623120). 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 ACADS protein function. 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. (less)
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196908.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Likely pathogenic (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004698926.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: ACADS: PM2, PM3, PP4, PS3:Supporting Number of individuals with the variant: 1

Comment:

Reported in association with SCAD deficiency in individuals with failure to thrive, feeding difficulties and hypotonia who were compound heterozygous for the G209S variant (Pedersen et al., 2008); In vitro functional studies demonstrated A199V had a damaging effect on SCAD protein. Functional studies with complex allele including A199V and G209S caused a severe effect (Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 28263315, 18523805)

Comment:

The ACADS c.596C>T variant is predicted to result in the amino acid substitution p.Ala199Val. This variant has been reported in patients with short chain acyl-coA dehydrogenase (SCAD) deficiency (Pedersen et al. 2008. PubMed ID: 18523805; Long et al. 2017. PubMed ID: 28263315). In experimental studies, the p.Ala199Val variant was shown to lead to defective tetramer formation and increased protein aggregation (Pedersen et al. 2008. PubMed ID: 18523805). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-121175763-C-T). This variant is interpreted as likely pathogenic.

Comment:

This variant is present in population databases (rs766579880, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 199 of the ACADS protein (p.Ala199Val). This missense change has been observed in individuals with clinical features of short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18523805, 28263315; Invitae). ClinVar contains an entry for this variant (Variation ID: 623120). 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 ACADS protein function. 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.

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
Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites.	Long T	Nature genetics	2017	PMID: 28263315
The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level.	Pedersen CB	Human genetics	2008	PMID: 18523805
-	-	-	-	PMID: 185223805

Text-mined citations for rs766579880 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000017.4(ACADS):c.596C>T (p.Ala199Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs766579880 ...