Submissions for variant NM_000019.4(ACAT1):c.1006-2A>C

gnomAD frequency: 0.00003  dbSNP: rs145229472

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002969	SCV000918381	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2018-01-02	criteria provided, single submitter	clinical testing	Variant summary: The ACAT1 c.1006-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 2/5 splicing predicting tools predict that this variant eliminates the 3' splicing acceptor site. This variant was found in 8/245964 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant has been reported in at least two patients in the compound heterozygous state (Fukao_2010). The brother of one of the patients has the same genotype, however, is asymptomatic at the age of 21.5, suggesting the variant of interest may associate with reduced penetrance or late onset of the disease (Grunert_2017). Functional studies showed this variant leads to skipping of exon 11 and a smaller protein product (Fukao_1992). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Department of Pediatrics, Gifu University	RCV000002969	SCV000966104	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Invitae	RCV000002969	SCV002151192	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-08-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2835). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 1346617). For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617). 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 (rs145229472, gnomAD 0.02%). This sequence change affects an acceptor splice site in intron 10 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).
GeneDx	RCV003329225	SCV004036810	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Published functional studies in vivo demonstrated that this variant results in aberrant splicing, leading to frameshift (Fukao T et al., 1992); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 28726122, 7173255, 25087612, 1346617)
Baylor Genetics	RCV000002969	SCV004212839	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-08-22	criteria provided, single submitter	clinical testing
OMIM	RCV000002969	SCV000023127	pathogenic	Deficiency of acetyl-CoA acetyltransferase	1992-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002969	SCV002086542	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2021-07-28	no assertion criteria provided	clinical testing