Variant summary: ACAT1 c.83_84delAT (p.Tyr28CysfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 241332 control chromosomes (gnomAD). c.83_84delAT has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Fukao_1997, Su_2017, Paquay_2017). These data indicate that the variant is very likely to be associated with disease. Fibroblasts obtained from a compound heterozygous individual carrying the variant of interest and another pathogenic variant showed very low levels of RNA and protein (Fukao_1997). Enzymatic activity measured in fibroblasts from homozygous individuals also showed reduced enzymatic activity (Paquay_2017). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000019.4(ACAT1):c.83_84del (p.Tyr28fs)
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.
(5)
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
5
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.83_84del (p.Tyr28fs)
Variation ID: 666463 Accession: VCV000666463.10
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 11q22.3 11: 108131915-108131916 (GRCh38) [ NCBI UCSC ] 11: 108002642-108002643 (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 Aug 31, 2019 Oct 20, 2024 Jun 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000019.4:c.83_84del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000010.1:p.Tyr28fs frameshift NM_000019.3:c.83_84delAT NM_001386677.1:c.83_84del NP_001373606.1:p.Tyr28fs frameshift NM_001386678.1:c.83_84del NP_001373607.1:p.Tyr28fs frameshift NM_001386679.1:c.-197AT[1] 5 prime UTR NM_001386681.1:c.-190AT[1] 5 prime UTR NM_001386682.1:c.-190AT[1] 5 prime UTR NM_001386685.1:c.-190AT[1] 5 prime UTR NM_001386686.1:c.-190AT[1] 5 prime UTR NM_001386687.1:c.-190AT[1] 5 prime UTR NM_001386688.1:c.-190AT[1] 5 prime UTR NM_001386689.1:c.-190AT[1] 5 prime UTR NM_001386690.1:c.-190AT[1] 5 prime UTR NM_001386691.1:c.-190AT[1] 5 prime UTR NR_170162.1:n.121AT[1] non-coding transcript variant NR_170163.1:n.215AT[1] non-coding transcript variant NC_000011.10:g.108131915AT[1] NC_000011.9:g.108002642AT[1] NG_009888.2:g.20211AT[1] LRG_1400:g.20211AT[1] LRG_1400t1:c.83_84del LRG_1400p1:p.Tyr28fs - Protein change
- Y28fs
- Other names
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- Canonical SPDI
- NC_000011.10:108131914:ATAT:AT
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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
Help
The frequency of the allele represented by this VCV record.
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- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000844768.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2024 | RCV004597878.3 |
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. |
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|---|---|---|---|---|---|
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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: SCV000966034.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Number of individuals with the variant: 4
Clinical Features:
Ketoacidosis (present) , Altered mental status (present)
Family history: yes
|
|
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Pathogenic
(Jun 08, 2020)
|
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: SCV001372352.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: ACAT1 c.83_84delAT (p.Tyr28CysfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ACAT1 c.83_84delAT (p.Tyr28CysfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 241332 control chromosomes (gnomAD). c.83_84delAT has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Fukao_1997, Su_2017, Paquay_2017). These data indicate that the variant is very likely to be associated with disease. Fibroblasts obtained from a compound heterozygous individual carrying the variant of interest and another pathogenic variant showed very low levels of RNA and protein (Fukao_1997). Enzymatic activity measured in fibroblasts from homozygous individuals also showed reduced enzymatic activity (Paquay_2017). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Oct 06, 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: SCV002237112.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr28Cysfs*38) in the ACAT1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr28Cysfs*38) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs749873354, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9090533). ClinVar contains an entry for this variant (Variation ID: 666463). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004212850.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005093071.3
First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024 |
Comment:
ACAT1: PVS1, PM2, PM3, PP4:Moderate
Number of individuals with the variant: 1
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Tyr28Cysfs*38) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs749873354, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9090533). ClinVar contains an entry for this variant (Variation ID: 666463). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACAT1: PVS1, PM2, PM3, PP4:Moderate
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: ACAT1 c.83_84delAT (p.Tyr28CysfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 241332 control chromosomes (gnomAD). c.83_84delAT has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Fukao_1997, Su_2017, Paquay_2017). These data indicate that the variant is very likely to be associated with disease. Fibroblasts obtained from a compound heterozygous individual carrying the variant of interest and another pathogenic variant showed very low levels of RNA and protein (Fukao_1997). Enzymatic activity measured in fibroblasts from homozygous individuals also showed reduced enzymatic activity (Paquay_2017). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr28Cysfs*38) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs749873354, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9090533). ClinVar contains an entry for this variant (Variation ID: 666463). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACAT1: PVS1, PM2, PM3, PP4:Moderate
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 and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. | Su L | Metabolic brain disease | 2017 | PMID: 28875337 |
| Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. | Paquay S | Journal of inherited metabolic disease | 2017 | PMID: 28255778 |
| Identification of three novel frameshift mutations (83delAT, 754insCT, and 435 + 1G to A) of mitochondrial acetoacetyl-coenzyme A thiolase gene in two Swiss patients with CRM-negative beta-ketothiolase deficiency. | Fukao T | Human mutation | 1997 | PMID: 9090533 |
| 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 |
Text-mined citations for rs749873354 ...
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 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.