PP3, PP4, PM3, PS3, PS4_moderate
ClinVar Genomic variation as it relates to human health
NM_001609.4(ACADSB):c.1159G>A (p.Glu387Lys)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001609.4(ACADSB):c.1159G>A (p.Glu387Lys)
Variation ID: 9203 Accession: VCV000009203.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q26.13 10: 123053091 (GRCh38) [ NCBI UCSC ] 10: 124812607 (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 Oct 26, 2024 Aug 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001609.4:c.1159G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001600.1:p.Glu387Lys missense NM_001330174.3:c.853G>A NP_001317103.1:p.Glu285Lys missense NC_000010.11:g.123053091G>A NC_000010.10:g.124812607G>A NG_008003.1:g.49179G>A LRG_451:g.49179G>A LRG_451t1:c.1159G>A LRG_451p1:p.Glu387Lys - Protein change
- E387K, E285K
- Other names
-
p.Glu387Lys
- Canonical SPDI
- NC_000010.11:123053090:G:A
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00027
1000 Genomes Project 30x 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00033
Exome Aggregation Consortium (ExAC) 0.00034
- Links
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. |
|||
| ACADSB | - | - |
GRCh38 GRCh37 |
306 | 365 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 6, 2024 | RCV000009781.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2023 | RCV001091421.28 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jan 27, 2020 | RCV001255064.2 |
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
(Nov 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226617.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM3, PS3, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235005.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000934644.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the ACADSB protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the ACADSB protein (p.Glu387Lys). This variant is present in population databases (rs188094280, gnomAD 0.05%). This missense change has been observed in individual(s) with 2-methylbutyryl-coenzyme A dehydrogenase deficiency (PMID: 17945527, 20547083; Invitae). ClinVar contains an entry for this variant (Variation ID: 9203). 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 not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247459.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Feb 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001522352.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001831798.5
First in ClinVar: Sep 08, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20547083); In silico analysis supports that this missense variant has a … (more)
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20547083); 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: 17945527, 30730842, 34426522, 32778825, 20547083, 36147814) (less)
|
|
|
Pathogenic
(Aug 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844871.2
First in ClinVar: Mar 26, 2023 Last updated: Oct 26, 2024 |
Comment:
Variant summary: ACADSB c.1159G>A (p.Glu387Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. … (more)
Variant summary: ACADSB c.1159G>A (p.Glu387Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature as a biallelic genotype in multiple clinically asymptomatic individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase/Short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, determined by elevated blood 2-methylbutyrylcarnitine (C5) and/or urine 2-methylbutyrylglycine (2MBG), often detected initially through newborn screening programs (e.g. Sass_2008, Alfardan_2010, Navarrete_2019, Rossi_2022). These data indicate that the variant is very likely to be associated with disease. When expressed in E. coli, the variant had minimal protein yield and 2% of normal WT activity (Alfardan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20547083, 30626930, 36147814, 17945527). ClinVar contains an entry for this variant (Variation ID: 9203). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 27, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Seizure
Affected status: yes
Allele origin:
paternal
|
New York Genome Center
Accession: SCV001431155.2
First in ClinVar: Sep 05, 2020 Last updated: Sep 05, 2020 |
Secondary finding: no
Method: whole genome sequencing
|
|
|
Pathogenic
(Jan 01, 2008)
|
no assertion criteria provided
Method: literature only
|
2-@METHYLBUTYRYL-CoA DEHYDROGENASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030002.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 13, 2020 |
Comment on evidence:
In a Turkish girl with 2-methylbutyryl-CoA dehydrogenase deficiency (610006), Sass et al. (2008) identified a homozygous 1159G-A transition in exon 10 of the ACADSB gene, … (more)
In a Turkish girl with 2-methylbutyryl-CoA dehydrogenase deficiency (610006), Sass et al. (2008) identified a homozygous 1159G-A transition in exon 10 of the ACADSB gene, resulting in a glu387-to-lys (E387K) substitution. She showed normal development at age 3 years. The E387K mutation was found in 2 of 146 Turkish control chromosomes and in 2 of 96 Lebanese control chromosomes, yielding an allelic frequency of about 2% in these populations. In vitro studies of patient fibroblasts confirmed an impairment in isoleucine degradation. In a child of European ancestry who was identified by newborn screening to have 2-methybutyryl-CoA dehydrogenase deficiency, Alfardan et al. (2010) identified compound heterozygosity for the E387K mutation and a thr148-to-ile (T148I; 600301.0004) mutation. Alfardan et al. (2010) introduced the E387K mutation into an SBCAD expression vector and expressed it in E. coli. SBCAD protein was not detectable by Western blot analysis, and SBCAD enzyme activity was absent. Molecular modeling suggested that the E387K mutation would disrupt a hydrogen binding conduit that was likely essential for monomer-monomer binding, and would also disrupt FAD binding, affecting enzyme stability. (less)
|
Comment:
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the ACADSB protein (p.Glu387Lys). This variant is present in population databases (rs188094280, gnomAD 0.05%). This missense change has been observed in individual(s) with 2-methylbutyryl-coenzyme A dehydrogenase deficiency (PMID: 17945527, 20547083; Invitae). ClinVar contains an entry for this variant (Variation ID: 9203). 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 not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20547083); 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: 17945527, 30730842, 34426522, 32778825, 20547083, 36147814)
Comment:
Variant summary: ACADSB c.1159G>A (p.Glu387Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature as a biallelic genotype in multiple clinically asymptomatic individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase/Short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, determined by elevated blood 2-methylbutyrylcarnitine (C5) and/or urine 2-methylbutyrylglycine (2MBG), often detected initially through newborn screening programs (e.g. Sass_2008, Alfardan_2010, Navarrete_2019, Rossi_2022). These data indicate that the variant is very likely to be associated with disease. When expressed in E. coli, the variant had minimal protein yield and 2% of normal WT activity (Alfardan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20547083, 30626930, 36147814, 17945527). ClinVar contains an entry for this variant (Variation ID: 9203). Based on the evidence outlined above, the variant was classified as 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:
PP3, PP4, PM3, PS3, PS4_moderate
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the ACADSB protein (p.Glu387Lys). This variant is present in population databases (rs188094280, gnomAD 0.05%). This missense change has been observed in individual(s) with 2-methylbutyryl-coenzyme A dehydrogenase deficiency (PMID: 17945527, 20547083; Invitae). ClinVar contains an entry for this variant (Variation ID: 9203). 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 not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20547083); 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: 17945527, 30730842, 34426522, 32778825, 20547083, 36147814)
Comment:
Variant summary: ACADSB c.1159G>A (p.Glu387Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature as a biallelic genotype in multiple clinically asymptomatic individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase/Short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, determined by elevated blood 2-methylbutyrylcarnitine (C5) and/or urine 2-methylbutyrylglycine (2MBG), often detected initially through newborn screening programs (e.g. Sass_2008, Alfardan_2010, Navarrete_2019, Rossi_2022). These data indicate that the variant is very likely to be associated with disease. When expressed in E. coli, the variant had minimal protein yield and 2% of normal WT activity (Alfardan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20547083, 30626930, 36147814, 17945527). ClinVar contains an entry for this variant (Variation ID: 9203). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-term monitoring for short/branched-chain acyl-CoA dehydrogenase deficiency: A single-center 4-year experience and open issues. | Rossi A | Frontiers in pediatrics | 2022 | PMID: 36147814 |
| The landscape of autosomal recessive variants in an isolated community: Implications for population screening for reproductive purposes. | Khayat M | Clinical genetics | 2021 | PMID: 34297361 |
| The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
| Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-CoA dehydrogenase deficiency: two new cases and review of literature. | Porta F | Journal of pediatric endocrinology & metabolism : JPEM | 2019 | PMID: 30730842 |
| 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 |
| Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. | Alfardan J | Molecular genetics and metabolism | 2010 | PMID: 20547083 |
| 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism. | Sass JO | Molecular genetics and metabolism | 2008 | PMID: 17945527 |
Text-mined citations for rs188094280 ...
HelpThese 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 27, 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.