NM_000019.4(ACAT1):c.120+1G>C AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 24, 2024
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:: RCV002017830.8

Allele description [Variation Report for NM_000019.4(ACAT1):c.120+1G>C]

NM_000019.4(ACAT1):c.120+1G>C

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.120+1G>C

HGVS:

NC_000011.10:g.108131955G>C
NG_009888.2:g.20251G>C
NM_000019.4:c.120+1G>CMANE SELECT
NM_001386677.1:c.120+1G>C
NM_001386678.1:c.120+1G>C
NM_001386679.1:c.-158+1G>C
NM_001386681.1:c.-151+1G>C
NM_001386682.1:c.-151+1G>C
NM_001386685.1:c.-151+1G>C
NM_001386686.1:c.-151+1G>C
NM_001386687.1:c.-151+1G>C
NM_001386688.1:c.-151+1G>C
NM_001386689.1:c.-151+1G>C
NM_001386690.1:c.-151+1G>C
NM_001386691.1:c.-151+1G>C
LRG_1400t1:c.120+1G>C
LRG_1400:g.20251G>C
NC_000011.9:g.108002682G>C

Links:

dbSNP: rs779908220

NCBI 1000 Genomes Browser:

rs779908220

Molecular consequence:

NM_000019.4:c.120+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386677.1:c.120+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386678.1:c.120+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386679.1:c.-158+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386681.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386682.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386685.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386686.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386687.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386688.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386689.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386690.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001386691.1:c.-151+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV002306155	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 7749408, 28492532
SCV004212872	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005680512	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002306155

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 5, 2023)

germline

clinical testing

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

SCV004212872

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2024)

unknown

clinical testing

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

SCV005680512

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 24, 2024)

germline

clinical testing

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

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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002306155.4

#	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 affects a donor splice site in intron 2 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 1509341). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	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, SCV004212872.2

#	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 Fulgent Genetics, Fulgent Genetics, SCV005680512.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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