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

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:

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

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

ACAT1:acetyl-CoA acetyltransferase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000019.4(ACAT1):c.433C>G (p.Gln145Glu)
  • NC_000011.10:g.108135240C>G
  • NG_009888.1:g.18710C>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
  • NM_000019.3:c.433C>G
Protein change:
Q145E; GLN145GLU
OMIM: 607809.0015; dbSNP: rs120074148
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000019.4:c.433C>G - missense variant - [Sequence Ontology: SO:0001583]


Deficiency of acetyl-CoA acetyltransferase
Alpha-methylacetoaceticaciduria; 2-methyl-3-hydroxybutyricacidemia; Mitochondrial acetoacetyl-CoA Thiolase deficiency; See all synonyms [MedGen]
MONDO: MONDO:0008760; MedGen: C1536500; Orphanet: 134; OMIM: 203750

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000023138OMIMno assertion criteria providedPathogenic
(Mar 1, 2002)
germlineliterature only

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

SCV000966056Department of Pediatrics, Gifu Universitycriteria provided, single submitter
Likely pathogenic
(May 5, 2019)

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

SCV001541608Invitaecriteria provided, single submitter
Uncertain significance
(Oct 19, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes11not providednot providedyesresearch
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



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]

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]
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000023138.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)


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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Department of Pediatrics, Gifu University, SCV000966056.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providedyesresearch PubMed (3)
2not providednot providednot providednot providedresearch PubMed (3)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided
2germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001541608.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


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 variant has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 11161836). ClinVar contains an entry for this variant (Variation ID: 2846). Experimental studies have shown that this variant affects ACAT1 protein 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 28, 2021

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