NM_000019.4(ACAT1):c.935T>C (p.Ile312Thr) AND Deficiency of acetyl-CoA acetyltransferase

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Apr 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:

Allele description [Variation Report for NM_000019.4(ACAT1):c.935T>C (p.Ile312Thr)]

NM_000019.4(ACAT1):c.935T>C (p.Ile312Thr)

ACAT1:acetyl-CoA acetyltransferase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000019.4(ACAT1):c.935T>C (p.Ile312Thr)
  • NC_000011.10:g.108142545T>C
  • NG_009888.1:g.26015T>C
  • NG_009888.2:g.30841T>C
  • NM_000019.4:c.935T>CMANE SELECT
  • NP_000010.1:p.Ile312Thr
  • LRG_1400t1:c.935T>C
  • LRG_1400:g.30841T>C
  • LRG_1400p1:p.Ile312Thr
  • NC_000011.9:g.108013272T>C
  • NM_000019.3:c.935T>C
  • P24752:p.Ile312Thr
Protein change:
I312T; ILE312THR
UniProtKB: P24752#VAR_007504; OMIM: 607809.0013; dbSNP: rs120074146
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000019.4:c.935T>C - 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)
SCV000023136OMIMno assertion criteria providedPathogenic
(Jan 1, 1998)
germlineliterature only

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

SCV000966096Department of Pediatrics, Gifu Universitycriteria provided, single submitter
Likely pathogenic
(May 5, 2019)

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

SCV001586092Invitaecriteria provided, single submitter
(Apr 3, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes32not providednot providedyesresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
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 (6)

Details of each submission

From OMIM, SCV000023136.2

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


In a Japanese patient (GK19) with mitochondrial acetoacetyl-Coa thiolase deficiency (203750), Fukao et al. (1998) identified compound heterozygous mutations in the ACAT1 gene: an asn93-to-ser (N93S; 607809.0012) substitution on one allele and an ile312-to-thr (I312T) substitution on the other.

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

From Department of Pediatrics, Gifu University, SCV000966096.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providedyesresearch PubMed (3)
2not providednot providednot providednot providedresearch PubMed (3)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not provided2not provided
2germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001586092.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


This sequence change replaces isoleucine with threonine at codon 312 of the ACAT1 protein (p.Ile312Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs120074146, ExAC 0.01%). This variant has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9744475, 25559898, 14518824). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2844). This variant has been reported to affect ACAT1 protein function (PMID: 9744475). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 14, 2021

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