NM_000019.4(ACAT1):c.1210C>T (p.Gln404Ter) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003500033.2

Allele description [Variation Report for NM_000019.4(ACAT1):c.1210C>T (p.Gln404Ter)]

NM_000019.4(ACAT1):c.1210C>T (p.Gln404Ter)

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.1210C>T (p.Gln404Ter)

HGVS:

NC_000011.10:g.108147316C>T
NG_009888.2:g.35612C>T
NM_000019.4:c.1210C>TMANE SELECT
NM_001386677.1:c.1231C>T
NM_001386678.1:c.895C>T
NM_001386679.1:c.913C>T
NM_001386681.1:c.940C>T
NM_001386682.1:c.940C>T
NM_001386685.1:c.940C>T
NM_001386686.1:c.940C>T
NM_001386687.1:c.940C>T
NM_001386688.1:c.940C>T
NM_001386689.1:c.940C>T
NM_001386690.1:c.940C>T
NM_001386691.1:c.940C>T
NP_000010.1:p.Gln404Ter
NP_001373606.1:p.Gln411Ter
NP_001373607.1:p.Gln299Ter
NP_001373608.1:p.Gln305Ter
NP_001373610.1:p.Gln314Ter
NP_001373611.1:p.Gln314Ter
NP_001373614.1:p.Gln314Ter
NP_001373615.1:p.Gln314Ter
NP_001373616.1:p.Gln314Ter
NP_001373617.1:p.Gln314Ter
NP_001373618.1:p.Gln314Ter
NP_001373619.1:p.Gln314Ter
NP_001373620.1:p.Gln314Ter
LRG_1400t1:c.1210C>T
LRG_1400:g.35612C>T
LRG_1400p1:p.Gln404Ter
NC_000011.9:g.108018043C>T
NR_170162.1:n.1185C>T
NR_170163.1:n.1243C>T

Protein change:

Q299*

Molecular consequence:

NR_170162.1:n.1185C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_170163.1:n.1243C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000019.4:c.1210C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386677.1:c.1231C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386678.1:c.895C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386679.1:c.913C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386681.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386682.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386685.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386686.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386687.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386688.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386689.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386690.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386691.1:c.940C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Deficiency of acetyl-CoA acetyltransferase
Synonyms:: Alpha-methylacetoaceticaciduria; 2-methyl-3-hydroxybutyricacidemia; 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
SCV004312842	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28689740, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004312842

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 9, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.

Grünert SC, Schmitt RN, Schlatter SM, Gemperle-Britschgi C, Balcı MC, Berg V, Çoker M, Das AM, Demirkol M, Derks TGJ, Gökçay G, Uçar SK, Konstantopoulou V, Christoph Korenke G, Lotz-Havla AS, Schlune A, Staufner C, Tran C, Visser G, Schwab KO, Fukao T, Sass JO.

Mol Genet Metab. 2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012. Epub 2017 Jun 27.

PubMed [citation]

PMID:: 28689740

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004312842.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant disrupts a region of the ACAT1 protein in which other variant(s) (p.Gly418Asp) have been determined to be pathogenic (PMID: 28689740; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with ACAT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln404*) in the ACAT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the ACAT1 protein. 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

Last Updated: Sep 29, 2024

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