Submissions for variant NM_000019.4(ACAT1):c.1124A>G (p.Asn375Ser)

gnomAD frequency: 0.00002  dbSNP: rs373771053

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pediatrics, Gifu University	RCV000844837	SCV000966117	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Invitae	RCV000844837	SCV001590397	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 375 of the ACAT1 protein (p.Asn375Ser). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a new termination codon (PMID: 18511318). However the mRNA is not expected to undergo nonsense-mediated decay. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. ClinVar contains an entry for this variant (Variation ID: 666528). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 18511318, 27928777, 30835345). 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 (rs373771053, gnomAD 0.009%).
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000844837	SCV002053773	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396461	SCV004105742	pathogenic	ACAT1-related disorder	2022-08-25	criteria provided, single submitter	clinical testing	The ACAT1 c.1124A>G variant is predicted to result in the amino acid substitution p.Asn375Ser. This variant has been reported in the homozygous state in at least two individuals with mitochondrial Acetoacetyl-CoA thiolase deficiency (Fukao et al 2008. PubMed ID: 18511318; Abdelkreem E et al 2017. PubMed ID: 27928777). Functional studies have shown that this variant activates a cryptic splice donor site 5 bases upstream from c.1124A>C within exon 11, causing aberrant splicing with a frameshift (Fukao et al. 2008. PubMed ID: 18511318). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108017047-A-G). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000844837	SCV004210386	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2024-03-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000844837	SCV002090054	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2021-08-05	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000844837	SCV004800845	pathogenic	Deficiency of acetyl-CoA acetyltransferase		no assertion criteria provided	clinical testing	PS3+PM2_P+PM3_S+PP4