NM_000019.4(ACAT1):c.433C>G (p.Gln145Glu) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 24, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000002980.14

Allele description [Variation Report for NM_000019.4(ACAT1):c.433C>G (p.Gln145Glu)]

NM_000019.4(ACAT1):c.433C>G (p.Gln145Glu)

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.433C>G (p.Gln145Glu)

HGVS:

NC_000011.10:g.108135240C>G
NG_009888.2:g.23536C>G
NM_000019.4:c.433C>GMANE SELECT
NP_000010.1:p.Gln145Glu
LRG_1400t1:c.433C>G
LRG_1400:g.23536C>G
LRG_1400p1:p.Gln145Glu
NC_000011.9:g.108005967C>G
NG_009888.1:g.18710C>G
NM_000019.3:c.433C>G

Protein change:

Q145E; GLN145GLU

Links:

OMIM: 607809.0015; dbSNP: rs120074148

NCBI 1000 Genomes Browser:

rs120074148

Molecular consequence:

NM_000019.4:c.433C>G - 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
SCV000023138	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000966056	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, 11914035, 31268215
SCV001541608	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 24, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11161836, 11914035, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023138

OMIM

no assertion criteria provided

Pathogenic
(Mar 1, 2002)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000966056

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]

SCV001541608

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 24, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000023138.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with T2 deficiency (203750), Fukao et al. (2002) identified a homozygous 433C-G transversion in the ACAT1 gene, resulting in a gln145-to-glu (Q145E) substitution. In vitro functional expression studies showed that the mutant protein had 15% residual activity at 37 degrees, which increased to 30% at 30 degrees. The findings indicated decreased heat stability of enzyme activity consistent with adverse effects on protein folding or dimerization.

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

From Department of Pediatrics, Gifu University, SCV000966056.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001541608.3

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

Description

This sequence change replaces glutamine with glutamic acid at codon 145 of the ACAT1 protein (p.Gln145Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs120074148, ExAC 0.009%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 11161836). ClinVar contains an entry for this variant (Variation ID: 2846). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ACAT1 function (PMID: 11914035). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Jan 13, 2025

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