ClinVar Genomic variation as it relates to human health
NM_001609.4(ACADSB):c.303+3A>G
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_001609.4(ACADSB):c.303+3A>G
Variation ID: 448980 Accession: VCV000448980.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.13 10: 123037850 (GRCh38) [ NCBI UCSC ] 10: 124797366 (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 Apr 6, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001609.4:c.303+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001330174.3:c.-3-2616A>G intron variant NC_000010.11:g.123037850A>G NC_000010.10:g.124797366A>G NG_008003.1:g.33938A>G LRG_451:g.33938A>G LRG_451t1:c.303+3A>G - Protein change
- Other names
- IVS3DS, A-G, +3
- Canonical SPDI
- NC_000010.11:123037849:A:G
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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 | ||
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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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ACADSB | - | - |
GRCh38 GRCh37 |
302 | 359 |
Conditions - Germline
Condition
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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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000009779.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 9, 2016 | RCV000522412.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2023 | RCV003419901.4 |
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
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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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Pathogenic
(Sep 09, 2016)
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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: SCV000616631.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The c.303+3A>G variant in the ACADSB gene has been reported previously in association with autosomal recessive short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) when present in the … (more)
The c.303+3A>G variant in the ACADSB gene has been reported previously in association with autosomal recessive short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) when present in the homozygous state or when in trans with another disease-causing variant (Kanavin et al., 2007; Madsen et al., 2006). This variant is predicted to destroy the natural splice donor site in intron 3. Functional studies demonstrate that the c.303+3A>G variant causes complete exon skipping of exon 3 (Madsen et al., 2006). We interpret c.303+3A>G as a disease-causing variant (less)
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Pathogenic
(Oct 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522353.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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ACADSB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116570.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ACADSB c.303+3A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in related and … (more)
The ACADSB c.303+3A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in related and unrelated individuals with 2-Methylbutyryl-CoA dehydrogenase deficiency (Matern D et al 2003. PubMed ID: 12837870; Madsen PP et al 2005. PubMed ID: 16317551; Kanavin OJ et al 2007. PubMed ID: 17883863). An in vitro study (minigene assay) showed this variant causes exon skipping (Madsen PP et al 2005. PubMed ID: 16317551). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-124797366-A-G). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002987490.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 3 of the ACADSB gene. It does not directly change the encoded amino acid sequence of the ACADSB protein. … (more)
This sequence change falls in intron 3 of the ACADSB gene. It does not directly change the encoded amino acid sequence of the ACADSB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with SBCAD deficiency (PMID: 12837870, 16317551, 30730842). ClinVar contains an entry for this variant (Variation ID: 448980). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16317551). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807701.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Feb 01, 2006)
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no assertion criteria provided
Method: literature only
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2-@METHYLBUTYRYL-CoA DEHYDROGENASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030000.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 13, 2020 |
Comment on evidence:
In a boy with 2-methylbutyryl glycinuria (610006), whose parents were from Somalia, Madsen et al. (2006) identified a homozygous A-to-G transition (c.303+3A-G) in intron 3 … (more)
In a boy with 2-methylbutyryl glycinuria (610006), whose parents were from Somalia, Madsen et al. (2006) identified a homozygous A-to-G transition (c.303+3A-G) in intron 3 of the ACADSB gene, resulting in the skipping of exon 3 as confirmed by mRNA analysis. The resultant mRNA likely leads to nonsense-mediated decay, but any residual protein was predicted to lack vital enzyme activity. Madsen et al. (2006) also identified the splice site mutation in 2 affected sibs previously reported by Gibson et al. (2000); see 600301.0002. (less)
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Pathogenic
(May 12, 2023)
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no assertion criteria provided
Method: clinical testing
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Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
biparental
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Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV004808389.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Uncertain significance
(Jun 20, 2022)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Deficiency of 2-methylbutyryl-CoA dehydrogenase
Affected status: yes
Allele origin:
inherited
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV003035479.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping. | Madsen PP | Human genetics | 2006 | PMID: 16317551 |
Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry. | Matern D | Pediatrics | 2003 | PMID: 12837870 |
2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism. | Gibson KM | Pediatric research | 2000 | PMID: 10832746 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs1345480688 ...
HelpRecord last updated Apr 06, 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.