NM_000019.4(ACAT1):c.1040T>C (p.Ile347Thr) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 6, 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:: RCV000844833.5

Allele description [Variation Report for NM_000019.4(ACAT1):c.1040T>C (p.Ile347Thr)]

NM_000019.4(ACAT1):c.1040T>C (p.Ile347Thr)

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.1040T>C (p.Ile347Thr)

HGVS:

NC_000011.10:g.108146236T>C
NG_009888.2:g.34532T>C
NM_000019.4:c.1040T>CMANE SELECT
NP_000010.1:p.Ile347Thr
LRG_1400t1:c.1040T>C
LRG_1400:g.34532T>C
LRG_1400p1:p.Ile347Thr
NC_000011.9:g.108016963T>C
NC_000011.9:g.108016963T>C
NG_009888.1:g.29706T>C
NM_000019.3:c.1040T>C

Protein change:

I347T

Links:

dbSNP: rs1338023969

NCBI 1000 Genomes Browser:

rs1338023969

Molecular consequence:

NM_000019.4:c.1040T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000966112	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31268215
SCV002230113	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15877211, 28689740, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000966112

Department of Pediatrics, Gifu University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 5, 2019)

germline

research

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

SCV002230113

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 6, 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	2	not provided	not provided	yes	research
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, SCV000966112.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	research	PubMed (2)
2	not provided	not provided	not provided	not provided	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	2	not provided
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002230113.3

#	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. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 15877211). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 347 of the ACAT1 protein (p.Ile347Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 15877211, 28689740). 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: 666524). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function.

#	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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