Variant summary: The ACAT1 c.1006-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 2/5 splicing predicting tools predict that this variant eliminates the 3' splicing acceptor site. This variant was found in 8/245964 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant has been reported in at least two patients in the compound heterozygous state (Fukao_2010). The brother of one of the patients has the same genotype, however, is asymptomatic at the age of 21.5, suggesting the variant of interest may associate with reduced penetrance or late onset of the disease (Grunert_2017). Functional studies showed this variant leads to skipping of exon 11 and a smaller protein product (Fukao_1992). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000019.4(ACAT1):c.1006-2A>C
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000019.4(ACAT1):c.1006-2A>C
Variation ID: 2835 Accession: VCV000002835.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108146200 (GRCh38) [ NCBI UCSC ] 11: 108016927 (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 Aug 15, 2015 Jun 17, 2024 Feb 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000019.4:c.1006-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001386677.1:c.1006-2A>C splice acceptor NM_001386678.1:c.691-2A>C splice acceptor NM_001386679.1:c.709-2A>C splice acceptor NM_001386681.1:c.736-2A>C splice acceptor NM_001386682.1:c.736-2A>C splice acceptor NM_001386685.1:c.736-2A>C splice acceptor NM_001386686.1:c.736-2A>C splice acceptor NM_001386687.1:c.736-2A>C splice acceptor NM_001386688.1:c.736-2A>C splice acceptor NM_001386689.1:c.736-2A>C splice acceptor NM_001386690.1:c.736-2A>C splice acceptor NM_001386691.1:c.736-2A>C splice acceptor NC_000011.10:g.108146200A>C NC_000011.9:g.108016927A>C NG_009888.2:g.34496A>C LRG_1400:g.34496A>C LRG_1400t1:c.1006-2A>C - Protein change
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- Other names
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IVS10, A-C, -2
- Canonical SPDI
- NC_000011.10:108146199:A:C
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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
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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. |
|||
| ACAT1 | - | - |
GRCh38 GRCh37 |
734 | 759 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000002969.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 19, 2023 | RCV003329225.1 |
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
(Jan 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918381.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The ACAT1 c.1006-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The ACAT1 c.1006-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 2/5 splicing predicting tools predict that this variant eliminates the 3' splicing acceptor site. This variant was found in 8/245964 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant has been reported in at least two patients in the compound heterozygous state (Fukao_2010). The brother of one of the patients has the same genotype, however, is asymptomatic at the age of 21.5, suggesting the variant of interest may associate with reduced penetrance or late onset of the disease (Grunert_2017). Functional studies showed this variant leads to skipping of exon 11 and a smaller protein product (Fukao_1992). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 05, 2019)
|
criteria provided, single submitter
Method: research
|
Deficiency of acetyl-CoA acetyltransferase
Affected status: yes
Allele origin:
germline
|
Department of Pediatrics, Gifu University
Accession: SCV000966104.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Number of individuals with the variant: 4
Clinical Features:
Ketoacidosis (present) , Neurological impairment (present)
Family history: yes
|
|
|
Pathogenic
(Sep 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004036810.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
Published functional studies in vivo demonstrated that this variant results in aberrant splicing, leading to frameshift (Fukao T et al., 1992); Canonical splice site variant … (more)
Published functional studies in vivo demonstrated that this variant results in aberrant splicing, leading to frameshift (Fukao T et al., 1992); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 28726122, 7173255, 25087612, 1346617) (less)
|
|
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Pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002151192.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 2835). Studies have shown that disruption of this splice site alters mRNA splicing and is expected … (more)
ClinVar contains an entry for this variant (Variation ID: 2835). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 1346617). For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs145229472, gnomAD 0.02%). This sequence change affects an acceptor splice site in intron 10 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). (less)
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004212839.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Feb 01, 1992)
|
no assertion criteria provided
Method: literature only
|
3-@KETOTHIOLASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023127.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 15, 2015 |
Comment on evidence:
For discussion of the splice site mutation in the ACAT1 gene (AG-to-CG transition at the 3-prime splice site of intron 10) that was found in … (more)
For discussion of the splice site mutation in the ACAT1 gene (AG-to-CG transition at the 3-prime splice site of intron 10) that was found in compound heterozygous state in a father and son with 3-ketothiolase deficiency (203750) by Fukao et al. (1992), see 607809.0002. (less)
|
|
|
Pathogenic
(Jul 28, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Alpha-methylacetoacetic aciduria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086542.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Published functional studies in vivo demonstrated that this variant results in aberrant splicing, leading to frameshift (Fukao T et al., 1992); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 28726122, 7173255, 25087612, 1346617)
Comment:
ClinVar contains an entry for this variant (Variation ID: 2835). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 1346617). For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs145229472, gnomAD 0.02%). This sequence change affects an acceptor splice site in intron 10 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408).
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:
Variant summary: The ACAT1 c.1006-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 2/5 splicing predicting tools predict that this variant eliminates the 3' splicing acceptor site. This variant was found in 8/245964 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant has been reported in at least two patients in the compound heterozygous state (Fukao_2010). The brother of one of the patients has the same genotype, however, is asymptomatic at the age of 21.5, suggesting the variant of interest may associate with reduced penetrance or late onset of the disease (Grunert_2017). Functional studies showed this variant leads to skipping of exon 11 and a smaller protein product (Fukao_1992). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Published functional studies in vivo demonstrated that this variant results in aberrant splicing, leading to frameshift (Fukao T et al., 1992); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 28726122, 7173255, 25087612, 1346617)
Comment:
ClinVar contains an entry for this variant (Variation ID: 2835). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 1346617). For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs145229472, gnomAD 0.02%). This sequence change affects an acceptor splice site in intron 10 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. | Abdelkreem E | Human mutation | 2019 | PMID: 31268215 |
| Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency. | Grünert SC | Molecular genetics and metabolism | 2017 | PMID: 28689740 |
| A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. | Fukao T | Molecular genetics and metabolism | 2010 | PMID: 20156697 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene. | Fukao T | Human mutation | 1995 | PMID: 7749408 |
| Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency. | Fukao T | The Journal of clinical investigation | 1992 | PMID: 1346617 |
Text-mined citations for rs145229472 ...
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 Sep 29, 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.