VCV000633029.10 - ClinVar

NM_000019.4(ACAT1):c.52dup (p.Leu18fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000019.4(ACAT1):c.52dup (p.Leu18fs)

Variation ID: 633029 Accession: VCV000633029.10

Type and length

Duplication, 1 bp

Location

Cytogenetic: 11q22.3 11: 108121653-108121654 (GRCh38) [ NCBI UCSC ] 11: 107992380-107992381 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 2, 2019	Jun 17, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000019.4:c.52dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000010.1:p.Leu18fs	frameshift
NM_000019.3:c.52dupC
NC_000011.10:g.108121658dup
NC_000011.9:g.107992385dup
NG_009888.2:g.9954dup
LRG_1400:g.9954dup
LRG_1400t1:c.52dup	LRG_1400p1:p.Leu18fs

... more HGVS ... less HGVS

Protein change

L18fs

Other names

Canonical SPDI

NC_000011.10:108121653:CCCCC:CCCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1476273214 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ACAT1		-	-	GRCh38 GRCh37	734	759

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deficiency of acetyl-CoA acetyltransferase	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 21, 2023	RCV000780811.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 18, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Deficiency of acetyl-CoA acetyltransferase Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918382.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (2) PubMed: 21669895‚ 15128923 Comment: Variant summary: The ACAT1 c.52dupC (p.Leu18ProfsX49) variant results in a premature termination codon, predicted to cause a truncated or absent ACAT1 protein due to nonsense … (more) Variant summary: The ACAT1 c.52dupC (p.Leu18ProfsX49) variant results in a premature termination codon, predicted to cause a truncated or absent ACAT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/142878 control chromosomes at a frequency of 0.000021, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). It has been reported in multiple affected individuals as compound heterozygotes, and pts fibroblast cells showed <15% of WT Enzyme activity (Zhang_2004, Saragoglou_2011, and paquay_ACAT1_JIMD_2017). Taken together, this variant is classified as pathogenic. (less)
Pathogenic (May 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Deficiency of acetyl-CoA acetyltransferase Affected status: yes Allele origin: germline	Department of Pediatrics, Gifu University Accession: SCV000966032.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Publications: PubMed (1) PubMed: 31268215 Number of individuals with the variant: 3 Clinical Features: Ketoacidosis (present) , Altered mental status (present) Family history: yes
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of acetyl-CoA acetyltransferase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001377776.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 7749408‚ 15128923‚ 21669895 Comment: This sequence change creates a premature translational stop signal (p.Leu18Profs49) in the ACAT1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu18Profs49) 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 (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with beta-ketothiolase deficiency (PMID: 15128923, 21669895). ClinVar contains an entry for this variant (Variation ID: 633029). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of acetyl-CoA acetyltransferase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210509.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

Variant summary: The ACAT1 c.52dupC (p.Leu18ProfsX49) variant results in a premature termination codon, predicted to cause a truncated or absent ACAT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/142878 control chromosomes at a frequency of 0.000021, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). It has been reported in multiple affected individuals as compound heterozygotes, and pts fibroblast cells showed <15% of WT Enzyme activity (Zhang_2004, Saragoglou_2011, and paquay_ACAT1_JIMD_2017). Taken together, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu18Profs*49) 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 (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with beta-ketothiolase deficiency (PMID: 15128923, 21669895). ClinVar contains an entry for this variant (Variation ID: 633029). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.	Abdelkreem E	Human mutation	2019	PMID: 31268215
Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening.	Sarafoglou K	Pediatrics	2011	PMID: 21669895
Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA.	Zhang GX	Pediatric research	2004	PMID: 15128923
Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene.	Fukao T	Human mutation	1995	PMID: 7749408

Text-mined citations for rs1476273214 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000019.4(ACAT1):c.52dup (p.Leu18fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1476273214 ...