VCV001509341.10 - ClinVar

NM_000019.4(ACAT1):c.120+1G>C

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (3); Uncertain significance (1)

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000019.4(ACAT1):c.120+1G>C

Variation ID: 1509341 Accession: VCV001509341.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108131955 (GRCh38) [ NCBI UCSC ] 11: 108002682 (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	Mar 28, 2022	Oct 3, 2026	Jul 18, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000019.4:c.120+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001386677.1:c.120+1G>C		splice donor
NM_001386678.1:c.120+1G>C		splice donor
NM_001386679.1:c.-158+1G>C		splice donor
NM_001386681.1:c.-151+1G>C		splice donor
NM_001386682.1:c.-151+1G>C		splice donor
NM_001386685.1:c.-151+1G>C		splice donor
NM_001386686.1:c.-151+1G>C		splice donor
NM_001386687.1:c.-151+1G>C		splice donor
NM_001386688.1:c.-151+1G>C		splice donor
NM_001386689.1:c.-151+1G>C		splice donor
NM_001386690.1:c.-151+1G>C		splice donor
NM_001386691.1:c.-151+1G>C		splice donor
NC_000011.10:g.108131955G>C
NC_000011.9:g.108002682G>C
NG_009888.2:g.20251G>C
LRG_1400:g.20251G>C
LRG_1400t1:c.120+1G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:108131954:G:C

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA228397423 dbSNP: rs779908220 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	840	868

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	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Jul 18, 2025	RCV002017830.10

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Jan 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Deficiency of acetyl-CoA acetyltransferase	Baylor Genetics Accession: SCV004212872.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (May 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Deficiency of acetyl-CoA acetyltransferase	Fulgent Genetics, Fulgent Genetics Accession: SCV005680512.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 05, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Deficiency of acetyl-CoA acetyltransferase	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002306155.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 16199547‚ 7749408 Comment: show This sequence change affects a donor splice site in intron 2 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 1509341). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jul 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Deficiency of acetyl-CoA acetyltransferase	Myriad Genetics, Inc. Accession: SCV008075147.1 First in ClinVar: Oct 03, 2026 Last updated: Oct 03, 2026	Comment: show NM_000019.3(ACAT1):c.120+1G>C is a variant in a canonical splice site classified as a variant of uncertain significance in the context of beta-ketothiolase deficiency. c.120+1G>C has not been observed in cases with relevant disease. Relevant functional assessments of this variant are not available in the literature. c.120+1G>C has not been observed in referenced population frequency databases. In summary, there is insufficient evidence to classify NM_000019.3(ACAT1):c.120+1G>C as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

This sequence change affects a donor splice site in intron 2 of the ACAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 1509341). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

NM_000019.3(ACAT1):c.120+1G>C is a variant in a canonical splice site classified as a variant of uncertain significance in the context of beta-ketothiolase deficiency. c.120+1G>C has not been observed in cases with relevant disease. Relevant functional assessments of this variant are not available in the literature. c.120+1G>C has not been observed in referenced population frequency databases. In summary, there is insufficient evidence to classify NM_000019.3(ACAT1):c.120+1G>C as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
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 rs779908220 ...

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 Oct 04, 2026