ClinVar Genomic variation as it relates to human health
NM_000019.4(ACAT1):c.377G>C (p.Cys126Ser)
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_000019.4(ACAT1):c.377G>C (p.Cys126Ser)
Variation ID: 666478 Accession: VCV000666478.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108135184 (GRCh38) [ NCBI UCSC ] 11: 108005911 (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 Feb 20, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000019.4:c.377G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000010.1:p.Cys126Ser missense NC_000011.10:g.108135184G>C NC_000011.9:g.108005911G>C NG_009888.2:g.23480G>C LRG_1400:g.23480G>C LRG_1400t1:c.377G>C LRG_1400p1:p.Cys126Ser - Protein change
- C126S
- Other names
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- Canonical SPDI
- NC_000011.10:108135183:G:C
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
718 | 741 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2023 | RCV000844783.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 9, 2023 | RCV003442119.1 |
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. |
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Likely pathogenic
(May 05, 2019)
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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: SCV000966051.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Ketoacidosis (present)
Family history: yes
Observation 2:
Method: Transient expression analysis of mutant cDNA
Result:
No detected mitochondrial acetoacetyl-CoA thiolase enzyme activity
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Likely pathogenic
(Jul 24, 2023)
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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: SCV004028807.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: ACAT1 c.377G>C (p.Cys126Ser) results in a non-conservative amino acid change located in the Thiolase, N-terminal (IPR020616) of the encoded protein sequence. Five of … (more)
Variant summary: ACAT1 c.377G>C (p.Cys126Ser) results in a non-conservative amino acid change located in the Thiolase, N-terminal (IPR020616) 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 4e-06 in 251396 control chromosomes. c.377G>C has been reported in the literature in a homozygous individual affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Abdelkreem_2019). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating abolishment of catalytic function (Abdelkreem_2019). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publication have been ascertained in the context of this evaluation (PMID: 31268215). All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(May 09, 2023)
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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: SCV004169903.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Reported as homozygous in a patient from a cohort reported to have mitochondrial acetoacetyl-CoA thiolase deficiency, but detailed clinical information was not provided (Abdelkreem et … (more)
Reported as homozygous in a patient from a cohort reported to have mitochondrial acetoacetyl-CoA thiolase deficiency, but detailed clinical information was not provided (Abdelkreem et al., 2019); Published functional studies demonstrate a damaging effect: loss of enzyme function (Abdelkreem et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31268215) (less)
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Likely pathogenic
(Sep 07, 2023)
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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:
unknown
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Baylor Genetics
Accession: SCV004210553.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 22, 2023)
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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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Invitae
Accession: SCV003456571.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 126 of the ACAT1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 126 of the ACAT1 protein (p.Cys126Ser). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of beta-ketothiolase deficiency (PMID: 31268215; Invitae). 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: 666478). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 31268215). For these reasons, this variant has been classified as Pathogenic. (less)
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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 |
Text-mined citations for rs1278227329 ...
HelpRecord last updated Mar 30, 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.