ClinVar Genomic variation as it relates to human health
NM_000019.4(ACAT1):c.1229C>T (p.Ala410Val)
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Likely pathogenic(3); Uncertain significance(2)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000019.4(ACAT1):c.1229C>T (p.Ala410Val)
Variation ID: 302210 Accession: VCV000302210.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108147335 (GRCh38) [ NCBI UCSC ] 11: 108018062 (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 Dec 6, 2016 Feb 25, 2025 Mar 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000019.4:c.1229C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000010.1:p.Ala410Val missense NC_000011.10:g.108147335C>T NC_000011.9:g.108018062C>T NG_009888.2:g.35631C>T LRG_1400:g.35631C>T LRG_1400t1:c.1229C>T LRG_1400p1:p.Ala410Val - Protein change
- A410V
- Other names
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- Canonical SPDI
- NC_000011.10:108147334:C:T
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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.
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The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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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ACAT1 | - | - |
GRCh38 GRCh37 |
768 | 793 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Conflicting classifications of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 24, 2024 | RCV000341325.15 |
Submissions - Germline
Classification
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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
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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
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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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Uncertain significance
(Jan 13, 2018)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000366985.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(May 05, 2019)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: research
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Deficiency of acetyl-CoA acetyltransferase
Affected status: yes
Allele origin:
germline
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Department of Pediatrics, Gifu University
Accession: SCV000966127.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Ketoacidosis (present)
Comment on clinical features:
Recurrent attacks of ketoacidosis
Test name: ACAT1 Mutational analysis
Family history: yes
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Likely pathogenic
(Mar 04, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002294161.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 410 of the ACAT1 protein (p.Ala410Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 410 of the ACAT1 protein (p.Ala410Val). This variant is present in population databases (rs767412638, gnomAD 0.08%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 28220263). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 302210). 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 ACAT1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Nov 17, 2022)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766006.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: ACAT1 c.1229C>T (p.Ala410Val) results in a non-conservative amino acid change located in the Thiolase, C-terminal domain (IPR020617) of the encoded protein sequence. Five … (more)
Variant summary: ACAT1 c.1229C>T (p.Ala410Val) results in a non-conservative amino acid change located in the Thiolase, C-terminal domain (IPR020617) 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 3.6e-05 in 251374 control chromosomes. c.1229C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with clinical and biochemical findings highly suggestive of Alpha-Methylacetoacetic Aciduria (beta-ketothiolase deficiency), a disease with a single genetic etiology (example, Nguyen_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; likely pathogenic, n=1). Based on the weigthing of the clinical evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Mar 24, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Deficiency of acetyl-CoA acetyltransferase
Affected status: unknown
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV005681166.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
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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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Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. | Abdelkreem E | Human mutation | 2019 | PMID: 31268215 |
Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years' experience of a medical center in northern Vietnam. | Nguyen KN | Journal of inherited metabolic disease | 2017 | PMID: 28220263 |
Text-mined citations for rs767412638 ...
HelpRecord last updated May 17, 2025
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.