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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000844794	SCV004046990	pathogenic	Deficiency of acetyl-CoA acetyltransferase		criteria provided, single submitter	clinical testing	The missense variant c.578T>C (p.Met193Thr) in ACAT1 gene has been reported in compound heterozygous state in individuals affected with mitochondrial acetoacetyl-CoA thiolase deficiency (Thümmler S. et al., 2010; Mrázová L. et al., 2005). Experimental studies have shown that this missense affects ACAT1 protein function (Mrázová L. et al., 2005). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Methionine at position 193 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.