VCV000002839.8 - ClinVar

NM_000019.4(ACAT1):c.1136G>T (p.Gly379Val)

Germline

Classification

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.

(3)

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.

Likely pathogenic

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.1136G>T (p.Gly379Val)

Variation ID: 2839 Accession: VCV000002839.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108146332 (GRCh38) [ NCBI UCSC ] 11: 108017059 (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	Apr 4, 2013	Feb 14, 2024	May 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000019.4:c.1136G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000010.1:p.Gly379Val	missense
NC_000011.10:g.108146332G>T
NC_000011.9:g.108017059G>T
NG_009888.2:g.34628G>T
LRG_1400:g.34628G>T
LRG_1400t1:c.1136G>T	LRG_1400p1:p.Gly379Val
	P24752:p.Gly379Val

... more HGVS ... less HGVS

Protein change

G379V

Other names

Canonical SPDI

NC_000011.10:108146331:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA252465 UniProtKB: P24752#VAR_007506 OMIM: 607809.0008 dbSNP: rs120074143 VarSome

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
Gene	OMIM	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.
Deficiency of acetyl-CoA acetyltransferase	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 10, 2023	RCV000002973.9

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.
Likely pathogenic (May 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Deficiency of acetyl-CoA acetyltransferase Affected status: yes Allele origin: germline	Department of Pediatrics, Gifu University Accession: SCV000966118.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Publications: PubMed (2) PubMed: 31268215‚ 7907600 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
Likely pathogenic (May 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of acetyl-CoA acetyltransferase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001486268.4 First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 7749408‚ 7907600 Comment: 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 … (more) 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. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 7749408). 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. ClinVar contains an entry for this variant (Variation ID: 2839). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 7907600). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 379 of the ACAT1 protein (p.Gly379Val). (less)
Pathogenic (Mar 01, 1994)	no assertion criteria provided Method: literature only	3-@KETOTHIOLASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023131.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 7907600‚ 1373235 Comment on evidence: Fukao et al. (1994) reported a Caucasian girl, born to nonconsanguineous parents, in whom the diagnosis of 3-ketothiolase deficiency (203750) was made when she was … (more) Fukao et al. (1994) reported a Caucasian girl, born to nonconsanguineous parents, in whom the diagnosis of 3-ketothiolase deficiency (203750) was made when she was 3 years old and after multiple ketoacidotic attacks. Her growth and development were normal, and there was no mental retardation. She was found to be a compound heterozygote; the maternal allele had a 1136G-to-T transversion, resulting in a gly379-to-val substitution (G379V) in the thiolase precursor. Cells transfected with cDNA carrying the G379V mutation showed no evidence of restored T2 activity. The paternal allele was associated with exon 8 skipping at the cDNA level. In the paternal allele at the gene level, a C-to-T transition causing a gln272-to-ter (Q272X) change was identified within exon 8, 13 bp from the 5-prime splice site of intron 8. Splicing experiments showed that the exonic mutation caused partial skipping of exon 8. This substitution was thought to alter the secondary structure of T2 pre-mRNA around exon 8 and thus impede normal splicing. They cited a similar situation reported by Steingrimsdottir et al. (1992), who detected aberrant splicing in the HGPRT (308000) gene resulting from a mutation located 13 nucleotides from the 5-prime splice site of intron 8 and causing exon 8 skipping in 90% of HGPRT transcripts. (less)

Comment:

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. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 7749408). 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. ClinVar contains an entry for this variant (Variation ID: 2839). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 7907600). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 379 of the ACAT1 protein (p.Gly379Val).

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:

Citations for germline classification of this variant

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
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 a novel exonic mutation at -13 from 5' splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency.	Fukao T	The Journal of clinical investigation	1994	PMID: 7907600
Mutations which alter splicing in the human hypoxanthine-guanine phosphoribosyltransferase gene.	Steingrimsdottir H	Nucleic acids research	1992	PMID: 1373235

Text-mined citations for rs120074143 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000019.4(ACAT1):c.1136G>T (p.Gly379Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs120074143 ...