NM_000019.4(ACAT1):c.414_415del (p.Leu140fs) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 23, 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:: RCV000844786.7

Allele description [Variation Report for NM_000019.4(ACAT1):c.414_415del (p.Leu140fs)]

NM_000019.4(ACAT1):c.414_415del (p.Leu140fs)

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.414_415del (p.Leu140fs)

HGVS:

NC_000011.10:g.108135221_108135222del
NG_009888.2:g.23517_23518del
NM_000019.4:c.414_415delMANE SELECT
NP_000010.1:p.Leu140fs
LRG_1400t1:c.414_415del
LRG_1400:g.23517_23518del
LRG_1400p1:p.Leu140fs
NC_000011.9:g.108005947_108005948del
NC_000011.9:g.108005948_108005949del
NG_009888.1:g.18691_18692del
NM_000019.3:c.414_415del

Protein change:

L140fs

Links:

dbSNP: rs1591363800

NCBI 1000 Genomes Browser:

rs1591363800

Molecular consequence:

NM_000019.4:c.414_415del - 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

Recent activity

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MAG: hypothetical protein [Bacteriophage sp.]
MAG: hypothetical protein [Bacteriophage sp.]
gi|2293575936|gb|UVX46633.1|

Protein
MAG: hypothetical protein, partial [Bacteriophage sp.]
MAG: hypothetical protein, partial [Bacteriophage sp.]
gi|2294908733|gb|UWD72841.1|

Protein
MAG: Bacteriophage sp. isolate 1979_37048, partial genome
MAG: Bacteriophage sp. isolate 1979_37048, partial genome
gi|2294906814|gb|OP076387.1|

Nucleotide
MAG: tail tube protein [Bacteriophage sp.]
MAG: tail tube protein [Bacteriophage sp.]
gi|2294105982|gb|UVY15820.1|

Protein
Taxonomy Links for SRA (Select 19080617) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000966054	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2019)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 31268215
SCV001591558	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7749408, 28255778, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000966054

Department of Pediatrics, Gifu University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 5, 2019)

germline

literature only

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

SCV001591558

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 23, 2023)

germline

clinical testing

PubMed (3)
[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	yes	2	1	not provided	not provided	yes	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (5)

Details of each submission

From Department of Pediatrics, Gifu University, SCV000966054.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	literature only	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 Invitae, SCV001591558.5

#	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 creates a premature translational stop signal (p.Leu140Tyrfs*36) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 666481). This premature translational stop signal has been observed in individual(s) with mitochondrial acetoacetyl-CoA thiolase deficiency (PMID: 28255778). This variant is not present in population databases (gnomAD no frequency).

#	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: Mar 30, 2024

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