NM_000019.4(ACAT1):c.890C>T (p.Thr297Met) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000844818.10

Allele description [Variation Report for NM_000019.4(ACAT1):c.890C>T (p.Thr297Met)]

NM_000019.4(ACAT1):c.890C>T (p.Thr297Met)

Gene:

ACAT1:acetyl-CoA acetyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000019.4(ACAT1):c.890C>T (p.Thr297Met)

HGVS:

NC_000011.10:g.108142500C>T
NG_009888.2:g.30796C>T
NM_000019.4:c.890C>TMANE SELECT
NP_000010.1:p.Thr297Met
LRG_1400t1:c.890C>T
LRG_1400:g.30796C>T
LRG_1400p1:p.Thr297Met
NC_000011.9:g.108013227C>T
NG_009888.1:g.25970C>T
NM_000019.3:c.890C>T
P24752:p.Thr297Met

Protein change:

T297M

Links:

UniProtKB: P24752#VAR_007502; dbSNP: rs886041122

NCBI 1000 Genomes Browser:

rs886041122

Molecular consequence:

NM_000019.4:c.890C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of acetyl-CoA acetyltransferase
Synonyms:: 3-KETOTHIOLASE DEFICIENCY; 3-OXOTHIOLASE DEFICIENCY; MITOCHONDRIAL ACETOACETYL-CoA THIOLASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008760; MedGen: C1536500; Orphanet: 134; OMIM: 203750

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000966094	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 5, 2019)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 7728148, 31268215
SCV001366905	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 29, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002169976	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28875337, 7728148, 28492532
SCV002600729	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004214733	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	yes	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

Abdelkreem E, Harijan RK, Yamaguchi S, Wierenga RK, Fukao T.

Hum Mutat. 2019 Oct;40(10):1641-1663. doi: 10.1002/humu.23831. Epub 2019 Jul 3. Review.

PubMed [citation]

PMID:: 31268215
PMCID:: PMC6790690

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, Li X, Lin R, Sheng H, Feng Z, Liu L.

Metab Brain Dis. 2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y. Epub 2017 Sep 5.

PubMed [citation]

PMID:: 28875337

See all PubMed Citations (5)

Details of each submission

From Department of Pediatrics, Gifu University, SCV000966094.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	1	not provided
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366905.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002169976.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr297 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28875337). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters ACAT1 gene expression (PMID: 7728148). 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: 279672). This missense change has been observed in individual(s) with mitochondrial acetoacetyl-CoA thiolase deficiency (PMID: 7728148). 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 (no rsID available, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 297 of the ACAT1 protein (p.Thr297Met).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600729.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: ACAT1 c.890C>T (p.Thr297Met) results in a non-conservative amino acid change located in the Thiolase, N-terminal domain (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 1.2e-05 in 251202 control chromosomes (gnomAD). c.890C>T has been reported in the literature in at least one compound heterozygous individual affected with Acetoacetyl-CoA Thiolase (T2) Deficiency (Wakazono_1995). These data do not allow any conclusion about variant significance. Wakazono_1995 also provided experimental evidence evaluating the variants impact on protein function, and reported that the variant has 10% residual activity. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004214733.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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