NM_000019.4(ACAT1):c.1190A>G (p.His397Arg) AND Deficiency of acetyl-CoA acetyltransferase

Clinical significance:Likely pathogenic (Last evaluated: Aug 4, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000019.4(ACAT1):c.1190A>G (p.His397Arg)]

NM_000019.4(ACAT1):c.1190A>G (p.His397Arg)

ACAT1:acetyl-CoA acetyltransferase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000019.4(ACAT1):c.1190A>G (p.His397Arg)
  • NC_000011.10:g.108147296A>G
  • NG_009888.2:g.35592A>G
  • NM_000019.4:c.1190A>GMANE SELECT
  • NM_001386677.1:c.1211A>G
  • NM_001386678.1:c.875A>G
  • NM_001386679.1:c.893A>G
  • NM_001386681.1:c.920A>G
  • NM_001386682.1:c.920A>G
  • NM_001386685.1:c.920A>G
  • NM_001386686.1:c.920A>G
  • NM_001386687.1:c.920A>G
  • NM_001386688.1:c.920A>G
  • NM_001386689.1:c.920A>G
  • NM_001386690.1:c.920A>G
  • NM_001386691.1:c.920A>G
  • NP_000010.1:p.His397Arg
  • NP_001373606.1:p.His404Arg
  • NP_001373607.1:p.His292Arg
  • NP_001373608.1:p.His298Arg
  • NP_001373610.1:p.His307Arg
  • NP_001373611.1:p.His307Arg
  • NP_001373614.1:p.His307Arg
  • NP_001373615.1:p.His307Arg
  • NP_001373616.1:p.His307Arg
  • NP_001373617.1:p.His307Arg
  • NP_001373618.1:p.His307Arg
  • NP_001373619.1:p.His307Arg
  • NP_001373620.1:p.His307Arg
  • LRG_1400t1:c.1190A>G
  • LRG_1400:g.35592A>G
  • LRG_1400p1:p.His397Arg
  • NC_000011.9:g.108018023A>G
  • NR_170162.1:n.1165A>G
  • NR_170163.1:n.1223A>G
Protein change:
Molecular consequence:
  • NM_000019.4:c.1190A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386677.1:c.1211A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386678.1:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386679.1:c.893A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386681.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386682.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386685.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386686.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386687.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386688.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386689.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386690.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386691.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_170162.1:n.1165A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_170163.1:n.1223A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]


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)
SCV001575698Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 4, 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



Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA.

Zhang GX, Fukao T, Rolland MO, Zabot MT, Renom G, Touma E, Kondo M, Matsuo N, Kondo N.

Pediatr Res. 2004 Jul;56(1):60-4. Epub 2004 May 5.

PubMed [citation]

The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.

Catanzano F, Ombrone D, Di Stefano C, Rossi A, Nosari N, Scolamiero E, Tandurella I, Frisso G, Parenti G, Ruoppolo M, Andria G, Salvatore F.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S91-4. doi: 10.1007/s10545-009-9028-3. Epub 2010 Feb 16.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001575698.1

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


This sequence change replaces histidine with arginine at codon 397 of the ACAT1 protein (p.His397Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACAT1-related conditions. 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. This variant disrupts the p.His397 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15128923, 20157782). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: May 14, 2021

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