NM_000019.4(ACAT1):c.997G>C (p.Ala333Pro) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Sep 5, 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:: RCV000002979.16

Allele description [Variation Report for NM_000019.4(ACAT1):c.997G>C (p.Ala333Pro)]

NM_000019.4(ACAT1):c.997G>C (p.Ala333Pro)

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.997G>C (p.Ala333Pro)

HGVS:

NC_000011.10:g.108144039G>C
NG_009888.2:g.32335G>C
NM_000019.4:c.997G>CMANE SELECT
NP_000010.1:p.Ala333Pro
LRG_1400t1:c.997G>C
LRG_1400:g.32335G>C
LRG_1400p1:p.Ala333Pro
NC_000011.9:g.108014766G>C
NG_009888.1:g.27509G>C
NM_000019.3:c.997G>C
P24752:p.Ala333Pro

Protein change:

A333P; ALA333PRO

Links:

UniProtKB: P24752#VAR_007505; OMIM: 607809.0014; dbSNP: rs120074147

NCBI 1000 Genomes Browser:

rs120074147

Molecular consequence:

NM_000019.4:c.997G>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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myelin-associated glycoprotein isoform a precursor [Homo sapiens]
myelin-associated glycoprotein isoform a precursor [Homo sapiens]
gi|11225258|ref|NP_002352.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023137	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000746954	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000966103	Department of Pediatrics, Gifu University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 5, 2019)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 9744475, 31268215
SCV001236935	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7749408, 9744475, 28875337, 28492532
SCV004021122	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28875337, 7749408, 34001203, 9744475 Citation Link,
SCV004212805	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2023)	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	germline	yes	2	2	not provided	not provided	yes	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	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

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

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000023137.3

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

Description

In a Japanese patient (GK01) with T2 deficiency (203750), Fukao et al. (1998) identified compound heterozygous mutations in the ACAT1 gene: an ala333-to-pro (A333P) substitution on one allele and a 1-bp deletion (149delC; 607809.0016) on the other.

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

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746954.2

#	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	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pediatrics, Gifu University, SCV000966103.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

#	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, SCV001236935.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 7749408). ClinVar contains an entry for this variant (Variation ID: 2845). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9744475, 28875337; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs120074147, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 333 of the ACAT1 protein (p.Ala333Pro).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004021122.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ACAT1 c.997G>C (p.Ala333Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR020617) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD, v2.1 Exomes dataset). c.997G>C has been reported in the literature in many compound heterozygous individuals, primarily of East Asian ancestry, affected with Alpha-Methylacetoacetic Aciduria (e.g., Fukao_1995, Fukao_1998, Su_2017, Lin_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant displayed no residual enzymatic activity (e.g., Fukao_1995, Fukao_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9744475, 7749408, 34001203, 28875337). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was 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, SCV004212805.1

#	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

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