Submissions for variant NM_000019.4(ACAT1):c.578T>C (p.Met193Thr)

dbSNP: rs541517496

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pediatrics, Gifu University	RCV000844794	SCV000966067	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Invitae	RCV000844794	SCV001401847	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with threonine at codon 193 of the ACAT1 protein (p.Met193Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with mitochondrial acetoacetyl-CoA thiolase deficiency (PMID: 15877211, 20046049). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 15877211). This variant disrupts the p.Met193 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23958592, 27928777). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000844794	SCV004046990	pathogenic	Deficiency of acetyl-CoA acetyltransferase		criteria provided, single submitter	clinical testing	The missense c.578T>Cp.Met193Thr variant in ACAT1 gene has been reported previously in compound heterozygous state in individuals affected with mitochondrial acetoacetyl-CoA thiolase deficiency Thümmler S et al., 2010. Experimental studies have shown that this missense change affects ACAT1 function Mrázová L et al., 2005. This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid Met at position 193 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Met193Thr in ACAT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.