NM_000019.4(ACAT1):c.622C>T (p.Arg208Ter) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Oct 6, 2025
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:: RCV000689417.17

Allele description [Variation Report for NM_000019.4(ACAT1):c.622C>T (p.Arg208Ter)]

NM_000019.4(ACAT1):c.622C>T (p.Arg208Ter)

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.622C>T (p.Arg208Ter)

HGVS:

NC_000011.10:g.108140107C>T
NG_009888.2:g.28403C>T
NM_000019.4:c.622C>TMANE SELECT
NP_000010.1:p.Arg208Ter
LRG_1400t1:c.622C>T
LRG_1400:g.28403C>T
LRG_1400p1:p.Arg208Ter
NC_000011.9:g.108010834C>T
NG_009888.1:g.23577C>T
NM_000019.3:c.622C>T

Protein change:

R208*

Links:

dbSNP: rs532190594

Molecular consequence:

NM_000019.4:c.622C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000817065	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7749408, 20156697, 28220263, 28492532
SCV000966070	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31268215
SCV001461795	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Sep 11, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002041661	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 21, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20156697, 34001203, 28220263 Citation Link,
SCV004210497	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004800856	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	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
not provided	germline	yes	31	28	not provided	not provided	yes	research
Miao	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene.

Fukao T, Yamaguchi S, Orii T, Hashimoto T.

Hum Mutat. 1995;5(2):113-20. Review.

PubMed [citation]

PMID:: 7749408

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (7)

PMC

bad uid value: PMC4544753: NCBI C++ Exception: Error: CORELIB(CStringException::eConvert) "/pubmed_gen/rbuild/version/20260106/cidx/2.10.3/src/corelib/ncbistr.cpp", line 973: ncbi::NStr::StringToUInt8() --- Cannot convert string 'PMC4544753' to Uint8 (m_Pos = 0)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000817065.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg208*) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs532190594, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with acetoacetyl-CoA-thiolase deficiency (PMID: 20156697, 28220263). It is commonly reported in individuals of Vietnamese ancestry (PMID: 20156697, 28220263). ClinVar contains an entry for this variant (Variation ID: 376832). For these reasons, this variant has been classified as 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 Department of Pediatrics, Gifu University, SCV000966070.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	31	not provided	yes	research	PubMed (2)

#	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		31	not provided	28	not provided

From Natera, Inc., SCV001461795.2

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

Description

The c.622C>T variant in ACAT1 is a nonsense variant predicted to introduce a stop codon at amino acid 208. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 28220263). Given the available evidence, this variant is classified as 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002041661.1

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

Description

Variant summary: ACAT1 c.622C>T (p.Arg208X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251186 control chromosomes. c.622C>T has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (example, Nguyen_2017, Fukao_2010, Lin_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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, SCV004210497.2

#	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

From Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800856.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Miao	1	not provided	not provided	clinical testing	not provided

Description

PS3+PM2_P+PM3_S+PP4

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

Last Updated: Apr 12, 2026

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