ClinVar Genomic variation as it relates to human health
NM_000017.4(ACADS):c.1138C>T (p.Arg380Trp)
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
-
NM_000017.4(ACADS):c.1138C>T (p.Arg380Trp)
Variation ID: 3837 Accession: VCV000003837.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.31 12: 120739347 (GRCh38) [ NCBI UCSC ] 12: 121177150 (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 Apr 4, 2013 Feb 14, 2024 Nov 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000017.4:c.1138C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000008.1:p.Arg380Trp missense NM_001302554.2:c.1126C>T NP_001289483.1:p.Arg376Trp missense NC_000012.12:g.120739347C>T NC_000012.11:g.121177150C>T NG_007991.1:g.18580C>T P16219:p.Arg380Trp - Protein change
- R380W, R376W
- Other names
- R356W
- p.R380W:CGG>TGG
- Canonical SPDI
- NC_000012.12:120739346:C:T
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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. |
|||
ACADS | - | - |
GRCh38 GRCh37 |
436 | 453 |
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/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Nov 18, 2023 | RCV000004041.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 13, 2023 | RCV000185699.3 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808371.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: no
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440546.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
|
|
Pathogenic
(Mar 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001547503.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Family history: no
Sex: male
Secondary finding: no
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033282.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
Likely pathogenic
(Feb 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002073760.1
First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022 |
Comment:
The c.1138C>T;p.(Arg380Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3837; PMID: 29678161; 24485985; 22424739; … (more)
The c.1138C>T;p.(Arg380Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3837; PMID: 29678161; 24485985; 22424739; 16926354; 11134486) - PS4. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24485985) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28940875 – gnomAD 0.0003941%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg380Trp) was detected in trans with a pathogenic variant (PMID: 24485985; 22424739; 16926354) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
Pathogenic
(Jun 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580934.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
|
|
Pathogenic
(Aug 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810482.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Likely pathogenic
(Jan 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238620.13
First in ClinVar: Jul 18, 2015 Last updated: Feb 07, 2023 |
Comment:
Functional studies found R380W is associated with no detectable ACADS enzyme activity (Corydon et al., 2001); In silico analysis supports that this missense variant has … (more)
Functional studies found R380W is associated with no detectable ACADS enzyme activity (Corydon et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as R356W due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 18523805, 14595061, 21483766, 16906473, 29678161, 24485985, 11134486, 22424739, 19800078, 16546179, 16926354, 32253862, 31589614, 32710939, 36499071, 33726816) (less)
|
|
Pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004121942.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: ACADS c.1138C>T (p.Arg380Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ACADS c.1138C>T (p.Arg380Trp) results in a non-conservative amino acid change in 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 9.3e-05 in 248232 control chromosomes (gnomAD). c.1138C>T has been reported in the literature in multiple individuals affected with short-chain acyl-CoA dehydrogenase (SCAD) deficiency (examples: Bok_2003, Edhager_2014, Navarrete_2019). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that this variant changes the normal protein function (examples: Edhager_2014, Bok_2003). The following publications have been ascertained in the context of this evaluation (PMID: 24485985, 30626930, 18523805, 14595061). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Nov 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000756744.6
First in ClinVar: May 03, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 380 of the ACADS protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 380 of the ACADS protein (p.Arg380Trp). This variant is present in population databases (rs28940875, gnomAD 0.05%). This missense change has been observed in individuals with SCAD deficiency (PMID: 11134486, 14595061, 16906473, 16926354, 22424739, 24485985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3837). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. Experimental studies have shown that this missense change affects ACADS function (PMID: 18523805). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 01, 2001)
|
no assertion criteria provided
Method: literature only
|
SCAD DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024207.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a girl with SCAD deficiency (201470) who presented in the neonatal period with hypotonia and seizures, Corydon et al. (2001) identified heterozygosity for a … (more)
In a girl with SCAD deficiency (201470) who presented in the neonatal period with hypotonia and seizures, Corydon et al. (2001) identified heterozygosity for a 1138C-T change in the SCAD gene, resulting in an arg356-to-trp (R359W) substitution. Expression studies in E. coli revealed undetectable SCAD activity for this mutant protein. The patient was also found to be heterozygous for the 625A variation (606885.0007). (less)
|
|
Pathogenic
(Oct 16, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220689.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program. | Navarrete R | European journal of human genetics : EJHG | 2019 | PMID: 30626930 |
An unusually high frequency of SCAD deficiency caused by two pathogenic variants in the ACADS gene and its relationship to the ethnic structure in Slovakia. | Lisyová J | BMC medical genetics | 2018 | PMID: 29678161 |
Proteomic investigation of cultivated fibroblasts from patients with mitochondrial short-chain acyl-CoA dehydrogenase deficiency. | Edhager AV | Molecular genetics and metabolism | 2014 | PMID: 24485985 |
Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. | Gallant NM | Molecular genetics and metabolism | 2012 | PMID: 22424739 |
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 |
Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. | van Maldegem BT | JAMA | 2006 | PMID: 16926354 |
Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy. | Merinero B | Journal of inherited metabolic disease | 2006 | PMID: 16906473 |
Short-chain Acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder. | Bok LA | Pediatrics | 2003 | PMID: 14595061 |
Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. | Corydon MJ | Pediatric research | 2001 | PMID: 11134486 |
Text-mined citations for rs28940875 ...
HelpRecord last updated Mar 17, 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.