NM_000019.4(ACAT1):c.1033_1034del (p.Glu345fs) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 9, 2023
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:: RCV000844832.6

Allele description [Variation Report for NM_000019.4(ACAT1):c.1033_1034del (p.Glu345fs)]

NM_000019.4(ACAT1):c.1033_1034del (p.Glu345fs)

Gene:

ACAT1:acetyl-CoA acetyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000019.4(ACAT1):c.1033_1034del (p.Glu345fs)

HGVS:

NC_000011.10:g.108146229_108146230del
NG_009888.2:g.34525_34526del
NM_000019.4:c.1033_1034delMANE SELECT
NP_000010.1:p.Glu345fs
LRG_1400t1:c.1033_1034del
LRG_1400:g.34525_34526del
LRG_1400p1:p.Glu345fs
NC_000011.9:g.108016955_108016956del
NC_000011.9:g.108016956_108016957del
NG_009888.1:g.29699_29700del
NM_000019.3:c.1033_1034del
NM_000019.3:c.1033_1034delGA

Protein change:

E345fs

Links:

dbSNP: rs781496140

NCBI 1000 Genomes Browser:

rs781496140

Molecular consequence:

NM_000019.4:c.1033_1034del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000966110	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
SCV002130322	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7749408, 28255778, 28492532
SCV004210542	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 9, 2023)	unknown	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

SCV000966110

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]

SCV002130322

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 10, 2023)

germline

clinical testing

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

SCV004210542

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 9, 2023)

unknown

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	yes	2	1	not provided	not provided	yes	research
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

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]

PMID:: 31268215
PMCID:: PMC6790690

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 (5)

Details of each submission

From Department of Pediatrics, Gifu University, SCV000966110.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002130322.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu345Argfs*9) 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 (rs781496140, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (aka mitochondrial acetoacetyl-CoA thiolase deficiency) (PMID: 28255778). ClinVar contains an entry for this variant (Variation ID: 524080).

#	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, SCV004210542.1

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

Last Updated: Sep 29, 2024

ClinVar

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