NM_000019.4(ACAT1):c.1160T>C (p.Ile387Thr) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 18, 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:: RCV000662283.8

Allele description [Variation Report for NM_000019.4(ACAT1):c.1160T>C (p.Ile387Thr)]

NM_000019.4(ACAT1):c.1160T>C (p.Ile387Thr)

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.1160T>C (p.Ile387Thr)

HGVS:

NC_000011.10:g.108146356T>C
NG_009888.2:g.34652T>C
NM_000019.4:c.1160T>CMANE SELECT
NP_000010.1:p.Ile387Thr
LRG_1400t1:c.1160T>C
LRG_1400:g.34652T>C
LRG_1400p1:p.Ile387Thr
NC_000011.9:g.108017083T>C
NG_009888.1:g.29826T>C
NM_000019.3:c.1160T>C

Protein change:

I387T

Links:

dbSNP: rs748303093

NCBI 1000 Genomes Browser:

rs748303093

Molecular consequence:

NM_000019.4:c.1160T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Homo sapiens blocked early in transport 1 homolog (S. cerevisiae)-like, mRNA (cD...
Homo sapiens blocked early in transport 1 homolog (S. cerevisiae)-like, mRNA (cDNA clone IMAGE:3349222)
gi|12653798|gb|BC000688.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000784611	Yale Center for Mendelian Genomics, Yale University	no assertion criteria provided	Pathogenic (Jul 20, 2017)	biparental	literature only	PubMed (1) [See all records that cite this PMID]
SCV000966120	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 5, 2019)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 31268215
SCV001461799	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002245533	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28726122, 28492532
SCV004210420	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 18, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	1	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	1	not provided	not provided	yes	literature only
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

Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.

Wojcik MH, Wierenga KJ, Rodan LH, Sahai I, Ferdinandusse S, Genetti CA, Towne MC, Peake RWA, James PM, Beggs AH, Brownstein CA, Berry GT, Agrawal PB.

JIMD Rep. 2018;39:45-54. doi: 10.1007/8904_2017_45. Epub 2017 Jul 20.

PubMed [citation]

PMID:: 28726122
PMCID:: PMC5953889

See all PubMed Citations (4)

Details of each submission

From Yale Center for Mendelian Genomics, Yale University, SCV000784611.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

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

From Department of Pediatrics, Gifu University, SCV000966120.1

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

From Natera, Inc., SCV001461799.1

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

#	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 Invitae, SCV002245533.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 387 of the ACAT1 protein (p.Ile387Thr). This variant is present in population databases (rs748303093, gnomAD 0.01%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 28726122). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACAT1 protein function. 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 Baylor Genetics, SCV004210420.2

#	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

Last Updated: Jun 17, 2024

ClinVar

Relating variation to medicine