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NM_000019.4(ACAT1):c.444_445del (p.Met148fs) AND Deficiency of acetyl-CoA acetyltransferase

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Feb 25, 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:
RCV000179238.16

Allele description [Variation Report for NM_000019.4(ACAT1):c.444_445del (p.Met148fs)]

NM_000019.4(ACAT1):c.444_445del (p.Met148fs)

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.444_445del (p.Met148fs)
HGVS:
  • NC_000011.10:g.108138906_108138907del
  • NG_009888.2:g.27202_27203del
  • NM_000019.4:c.444_445delMANE SELECT
  • NP_000010.1:p.Met148fs
  • LRG_1400t1:c.444_445del
  • LRG_1400:g.27202_27203del
  • LRG_1400p1:p.Met148fs
  • NC_000011.9:g.108009633_108009634del
  • NG_009888.1:g.22376_22377del
  • NM_000019.3:c.444_445del
  • NM_000019.3:c.444_445delGG
Protein change:
M148fs
Links:
dbSNP: rs727503795
NCBI 1000 Genomes Browser:
rs727503795
Molecular consequence:
  • NM_000019.4:c.444_445del - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000693969Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Dec 19, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000829085Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 11, 2024)
germlineclinical testing

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

SCV004210520Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 25, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Development and performance of a comprehensive targeted sequencing assay for pan-ethnic screening of carrier status.

Tanner AK, Valencia CA, Rhodenizer D, Espirages M, Da Silva C, Borsuk L, Caldwell S, Gregg E, Grimes E, Lichanska AM, Morris L, Purkayastha A, Weslowski B, Tibbetts C, Lorence MC, Hegde M.

J Mol Diagn. 2014 May;16(3):350-60. doi: 10.1016/j.jmoldx.2013.12.003. Epub 2014 Feb 8.

PubMed [citation]
PMID:
24517888

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 (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000693969.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: ACAT1 c.444_445delGG (p.Met148IlefsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251452 control chromosomes. c.444_445delGG has been reported in the literature in one heterozygote individual evaluated on a pan-ethnic carrier screening assay with no additional information provided (example, Tanner_2014). This report does not provide unequivocal conclusions about the phenotypic association of the variant in an individual affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency. Although based on loss of function as an established mechanism of disease in individuals with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency, this variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000829085.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Met148Ilefs*28) 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 (rs727503795, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 166649). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004210520.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 17, 2024