ClinVar Genomic variation as it relates to human health
NM_000017.4(ACADS):c.529T>C (p.Trp177Arg)
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.529T>C (p.Trp177Arg)
Variation ID: 3828 Accession: VCV000003828.63
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.31 12: 120737893 (GRCh38) [ NCBI UCSC ] 12: 121175696 (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 Sep 16, 2024 Jun 11, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000017.4:c.529T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000008.1:p.Trp177Arg missense NM_001302554.2:c.473-156T>C intron variant NC_000012.12:g.120737893T>C NC_000012.11:g.121175696T>C NG_007991.1:g.17126T>C P16219:p.Trp177Arg - Protein change
- W177R
- Other names
- W153R
- p.W177R:TGG>CGG
- Canonical SPDI
- NC_000012.12:120737892:T:C
-
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.
-
0.00200 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00045
Exome Aggregation Consortium (ExAC) 0.00055
1000 Genomes Project 0.00200
The Genome Aggregation Database (gnomAD) 0.00202
Trans-Omics for Precision Medicine (TOPMed) 0.00206
1000 Genomes Project 30x 0.00265
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 |
438 | 457 |
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 (14) |
criteria provided, multiple submitters, no conflicts
|
Jun 11, 2024 | RCV000004032.39 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2022 | RCV000185684.16 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 9, 2021 | RCV002512732.9 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580354.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM3, PM2_SUP, PP1, PP3
|
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(Nov 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238605.15
First in ClinVar: Jul 18, 2015 Last updated: Dec 03, 2022 |
Comment:
Reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency using alternative nomenclature (Gregersen et al., 1998); Functional analysis found that this variant is … (more)
Reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency using alternative nomenclature (Gregersen et al., 1998); Functional analysis found that this variant is associated with significantly reduced enzyme activity compared to wild-type (Gregersen et al., 1998); 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: 18523805, 12736383, 28263315, 16546179, 18676165, 22241096, 23798014, 22424739, 9499414, 31589614, 31813752, 32778825) (less)
|
|
Likely pathogenic
(Aug 22, 2014)
|
criteria provided, single submitter
Method: literature only
|
Deficiency of butyryl-CoA dehydrogenase
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220594.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611158.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Sep 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807320.2
First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
Pathogenic
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004223890.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3
Number of individuals with the variant: 5
|
|
Pathogenic
(Oct 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021051.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000632509.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 177 of the ACADS protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 177 of the ACADS protein (p.Trp177Arg). This variant is present in population databases (rs57443665, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with SCAD deficiency (PMID: 9499414, 12736383, 18676165, 22241096). ClinVar contains an entry for this variant (Variation ID: 3828). 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, 18523805). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847349.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Trp177Arg variant in ACADS has been reported in the homozygous state in at least 7 individuals and in the compound heterozygous state in 11 … (more)
The p.Trp177Arg variant in ACADS has been reported in the homozygous state in at least 7 individuals and in the compound heterozygous state in 11 individuals with short chain acyl-CoA dehydrogenase deficiency (SCADD) that was detected from biochemical evaluations; however, many of these individuals were asymptomatic at the time of study (Gregersen 1998 PMID: 9499414, Koeberl 2003 PMID: 12736383, Waisbren 2008 PMID: 18676165, Pena 2012 PMID: 22241096, Maguolo 2020 PMID: 32793418, Sadat 2020 PMID: 31813752). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3828) and has been identified in 0.6% (261/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), including 3 homozygotes, which is consistent with the frequency and manifestation of SCADD in the generation population. In vitro functional studies provide evidence that this variant reduces enzyme activity (Gregersen 1998 PMID: 9499414) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive SCADD. ACMG/AMP Criteria applied: PM3_Strong, PP3, PS3_Supporting, PP4. (less)
|
|
Pathogenic
(Jun 11, 2024)
|
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: SCV005204460.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: ACADS c.529T>C (p.Trp177Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. … (more)
Variant summary: ACADS c.529T>C (p.Trp177Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 0.00045 in 251254 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADS causing Deficiency Of Butyryl-CoA Dehydrogenase, allowing no conclusion about variant significance. c.529T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (example: Gregerson_1998, Koeberl_2003, Waisbren_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gregerson_1998). The following publications have been ascertained in the context of this evaluation (PMID: 12736383, 18676165, 9499414). ClinVar contains an entry for this variant (Variation ID: 3828). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jan 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000703978.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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: SCV002033278.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
Pathogenic
(Jul 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002548619.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
The homozygous c.529T>C (p.Trp177Arg) variant identified in the ACADS gene substitutes a well conserved Tryptophan for Arginine at amino acid177/413 (exon 5/10). This variant is … (more)
The homozygous c.529T>C (p.Trp177Arg) variant identified in the ACADS gene substitutes a well conserved Tryptophan for Arginine at amino acid177/413 (exon 5/10). This variant is found with appreciable frequency in gnomAD (279 heterozygotes, 3 homozygotes; allele frequency:1.83e-3). In silico algorithms predict it to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.957) to the function of the canonical transcript. This variant is reported as LikelyPathogenic/Pathogenic in ClinVar (VarID:3828) and has been reported in many individuals in the literature with biochemical findings consistent with SCADD [PMID:9499414, 18523805, 23798014, others]. Functional studies suggest it significantly impairs enzyme activity [PMID:9499414]. The homozygous c.529T>C(p.Trp177Arg) variant identified in the ACADS gene is reported as Pathogenic. (less)
Clinical Features:
Intellectual disability (present) , Autism (present) , Elevated circulating creatine kinase concentration (present) , Rhabdomyolysis (present)
Secondary finding: no
|
|
Pathogenic
(Jul 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003584295.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.529T>C (p.W177R) alteration is located in exon 5 (coding exon 5) of the ACADS gene. This alteration results from a T to C substitution … (more)
The c.529T>C (p.W177R) alteration is located in exon 5 (coding exon 5) of the ACADS gene. This alteration results from a T to C substitution at nucleotide position 529, causing the tryptophan (W) at amino acid position 177 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the ACADS c.529T>C alteration was observed in 0.06% (174/282582) of total alleles studied, with a frequency of 0.67% (168/24930) in the African subpopulation. This alteration has been reported as homozygous and compound heterozygous in multiple individuals with biochemical diagnoses of short-chain acyl-CoA dehydrogenase deficiency (Waisbren, 2008; Pedersen, 2008; Gregersen, 1998; Koeberl, 2003; Pena, 2012; Maguolo, 2020). This amino acid position is highly conserved in available vertebrate species. In a ferricenium ion-based enzyme activity assay, this alteration had no detectable activity above background (Gregersen, 1998) The p.W177R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Dec 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005049838.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
Pathogenic
(May 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV005200816.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Comment:
PS3, PM3_Very Strong
|
|
Pathogenic
(Apr 01, 1998)
|
no assertion criteria provided
Method: literature only
|
SCAD DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024198.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
See 606885.0003 and Gregersen et al. (1998).
|
|
Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142438.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000017.2:c.529T>C in the ACADS gene has an allele frequency of 0.007 in Africa subpopulation in the gnomAD database. Functional studies demonstrate that c.529T>C has affected … (more)
NM_000017.2:c.529T>C in the ACADS gene has an allele frequency of 0.007 in Africa subpopulation in the gnomAD database. Functional studies demonstrate that c.529T>C has affected aggregation and abolishes enzymatic activity of the encoded protein (PMID: 9499414; 18523805). It was detected in multiple individuals with autosomal recessive Deficiency of butyryl-CoA dehydrogenase, two homozygous c.529T>C (p.Trp177Arg), compound heterozygous with c.988C>T (p.Arg330Cys) (PMID: 22241096; 18676165; 12736383). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4. (less)
|
|
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 |
---|---|---|---|---|
Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience. | Maguolo A | Molecular genetics and metabolism reports | 2020 | PMID: 32793418 |
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 |
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 |
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms. | Waisbren SE | Molecular genetics and metabolism | 2008 | PMID: 18676165 |
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 |
Understanding mutations and protein stability through tripeptides. | Anishetty S | FEBS letters | 2006 | PMID: 16546179 |
Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. | Koeberl DD | Pediatric research | 2003 | PMID: 12736383 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADS | - | - | - | - |
Text-mined citations for rs57443665 ...
HelpRecord last updated Sep 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.