ClinVar Genomic variation as it relates to human health
NM_000017.4(ACADS):c.1147C>T (p.Arg383Cys)
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
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NM_000017.4(ACADS):c.1147C>T (p.Arg383Cys)
Variation ID: 3829 Accession: VCV000003829.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120739356 (GRCh38) [ NCBI UCSC ] 12: 121177159 (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 Apr 4, 2013 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000017.4:c.1147C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000008.1:p.Arg383Cys missense NM_001302554.2:c.1135C>T NP_001289483.1:p.Arg379Cys missense NC_000012.12:g.120739356C>T NC_000012.11:g.121177159C>T NG_007991.1:g.18589C>T P16219:p.Arg383Cys - Protein change
- R383C, R379C
- Other names
- R359C
- p.R383C:CGC>TGC
- Canonical SPDI
- NC_000012.12:120739355:C:T
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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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00012
Exome Aggregation Consortium (ExAC) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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ACADS | - | - |
GRCh38 GRCh37 |
434 | 454 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000004033.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2023 | RCV000185700.7 |
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
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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
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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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Likely pathogenic
(Dec 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915578.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ACADS c.1147C>T (p.Arg383Cys) missense variant has been reported in at least five studies and is found in a total of eight individuals with SCAD … (more)
The ACADS c.1147C>T (p.Arg383Cys) missense variant has been reported in at least five studies and is found in a total of eight individuals with SCAD deficiency including in one in a homozygous state, four in a compound heterozygous state, and three in a heterozygous state (Gregersen et al. 1998; Corydon et al. 2001; Pedersen et al. 2008; Dessein et al. 2017; Kilic et al. 2017). All of the compound heterozygous individuals also carried a c.625G>A variant in a homozygous or heterozygous state. The p.Arg383Cys variant was absent from 248 healthy controls and is reported at a frequency of 0.000681 in the African American population of the Exome Sequencing Project. Pedersen et al. (2003) found thep.Arg383Cys variant caused severely impaired folding and exhibited an increased dependence on the hsp60 machinery and remained associated with the hsp60 complex for longer periods of time than wild type protein. Based on the evidence, the p.Arg383Cys variant is classified as likely pathogenic for SCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002033283.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768745.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A heterozygous missense variant was identified, NM_000017.3(ACADS):c.1147C>T in exon 10 of 10 of the ACADS gene. This substitution is predicted to create a major amino … (more)
A heterozygous missense variant was identified, NM_000017.3(ACADS):c.1147C>T in exon 10 of 10 of the ACADS gene. This substitution is predicted to create a major amino acid change from arginine to cysteine at position 383 of the protein, NP_000008.1 (ACADS):p.(Arg383Cys). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the Acyl-CoA dehydrogenase C-term domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.009% (26 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in patients with deficiency of short-chain acyl-CoA dehydrogenase (ClinVar; Gregersen, N. et al. (1998); Pedersen, C.B. et al. (2008); Corydon, M.J. et al. (2001); Waisbren, S.E. et al. (2013); Pena, L. et al. (2012)). In addition, studies show that this variant impacts protein function (Pedersen, C.B. et al. (2008); Gregersen, N. et al. (1998)). A different variant in the same codon resulting in a change to histidine has been reported VUS (ClinVar; Gregersen, N. et al. (2008)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
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Likely pathogenic
(Feb 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800611.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000238621.15
First in ClinVar: Jul 18, 2015 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate severely impaired folding and higher degradation rate compared to wildtype, supporting a damaging effect (Pedersen et al., 2003); In silico analysis … (more)
Published functional studies demonstrate severely impaired folding and higher degradation rate compared to wildtype, supporting a damaging effect (Pedersen et al., 2003); 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: 25670805, 26990548, 9499414, 28532786, 18523805, 22241096, 16926354, 11134486, 23798014, 30035407, 31980526, 14506246, 34426522, 31589614, 31813752, 33726816, 32778825, 27535533) (less)
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine
Accession: SCV004176645.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000632500.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 383 of the ACADS protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 383 of the ACADS protein (p.Arg383Cys). This variant is present in population databases (rs28940872, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-CoA dehydrogenase deficiency (PMID: 11134486, 16926354, 22241096, 30035407, 31813752; Invitae). This variant is also known as R359C. ClinVar contains an entry for this variant (Variation ID: 3829). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9499414, 14506246, 18523805). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2001)
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no assertion criteria provided
Method: literature only
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SCAD DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024199.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with SCAD deficiency (201470), Gregersen et al. (1998) found compound heterozygosity for a 511C-T point mutation in 1 allele (resulting in an … (more)
In a patient with SCAD deficiency (201470), Gregersen et al. (1998) found compound heterozygosity for a 511C-T point mutation in 1 allele (resulting in an arg147-to-trp amino acid substitution) and, in the other allele, an 1147C-T mutation (resulting in an arg359-to-cys amino acid substitution) together with the 625G-A polymorphism that is found in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). The 1147C-T mutation was not present in 98 normal alleles, but was detected in 3 alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. In a girl with SCAD deficiency and low average IQ, Corydon et al. (2001) found heterozygosity for the 1147C-T change as well as homozygosity for the 625G-A variation (606885.0007). (less)
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Likely pathogenic
(Mar 14, 2017)
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no assertion criteria provided
Method: clinical testing
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Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000678045.2
First in ClinVar: Jan 06, 2018 Last updated: Aug 13, 2019 |
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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 |
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Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia. | Sadat R | Molecular genetics and metabolism | 2020 | PMID: 31813752 |
Microcephaly and developmental delay caused by short-chain acyl-CoA dehydrogenase deficiency. | Kılıç M | The Turkish journal of pediatrics | 2017 | PMID: 30035407 |
Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants. | Dessein AF | Clinica chimica acta; international journal of clinical chemistry | 2017 | PMID: 28532786 |
Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms. | Nochi Z | Journal of inherited metabolic disease | 2017 | PMID: 28516284 |
Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. | Waisbren SE | Developmental disabilities research reviews | 2013 | PMID: 23798014 |
Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience. | Pena L | Genetics in medicine : official journal of the American College of Medical Genetics | 2012 | PMID: 22241096 |
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 |
Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. | Pedersen CB | The Journal of biological chemistry | 2003 | PMID: 14506246 |
Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. | Corydon MJ | Pediatric research | 2001 | PMID: 11134486 |
Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria. | Gregersen N | Human molecular genetics | 1998 | PMID: 9499414 |
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Text-mined citations for rs28940872 ...
HelpRecord last updated Feb 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.