Submissions for variant NM_000019.4(ACAT1):c.1160T>C (p.Ile387Thr)

gnomAD frequency: 0.00001  dbSNP: rs748303093

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493456	SCV000582426	likely pathogenic	not provided	2015-10-02	criteria provided, single submitter	clinical testing	The I387T variant in the ACAT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I387T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I387T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G379V, A380T, S390P, H397D) have been reported in the Human Gene Mutation Database in association with acetoacetyl-CoA thiolase deficiency (also known as alpha-methylacetoacetic aciduria) (Stenson et al., 2014), supporting the functional importance of this region of the protein. The I387T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded
Department of Pediatrics, Gifu University	RCV000662283	SCV000966120	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000662283	SCV002245533	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 387 of the ACAT1 protein (p.Ile387Thr). This variant is present in population databases (rs748303093, gnomAD 0.01%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 28726122). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429773). 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) performed at Invitae indicates that this missense variant is expected to disrupt ACAT1 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000662283	SCV004210420	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2024-01-18	criteria provided, single submitter	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000662283	SCV000784611	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2017-07-20	no assertion criteria provided	literature only
Natera, Inc.	RCV000662283	SCV001461799	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2020-09-16	no assertion criteria provided	clinical testing