ClinVar Genomic variation as it relates to human health

The T297M missense change in the ACAT1 gene has been reported previously in association with beta-ketothiolase deficiency in an individual who presented with a severe ketoacidotic attack who harbored another pathogenic missense variant on the opposite ACAT1 allele (in trans) (Fukao et al., 1995). In vivo expression studies found that T297M is associated with approximately 10% residual beta-ketothiolase enzyme activity (Fukao et al., 1995). The T297M 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 T297M 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. In summary we interpret T297M to be pathogenic.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.

Variant summary: ACAT1 c.890C>T (p.Thr297Met) results in a non-conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251202 control chromosomes (gnomAD). c.890C>T has been reported in the literature in at least one compound heterozygous individual affected with Acetoacetyl-CoA Thiolase (T2) Deficiency (Wakazono_1995). These data do not allow any conclusion about variant significance. Wakazono_1995 also provided experimental evidence evaluating the variants impact on protein function, and reported that the variant has 10% residual activity. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr297 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28875337). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters ACAT1 gene expression (PMID: 7728148). 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. ClinVar contains an entry for this variant (Variation ID: 279672). This missense change has been observed in individual(s) with mitochondrial acetoacetyl-CoA thiolase deficiency (PMID: 7728148). 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 (no rsID available, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 297 of the ACAT1 protein (p.Thr297Met).

ACAT1: PM2, PM3, PM5, PP3

The ACAT1 c.890C>T variant is predicted to result in the amino acid substitution p.Thr297Met. This variant has been reported in the compound heterozygous state in an individual with acetoacetyl-CoA thiolase deficiency (Fukao et al. 1995. PubMed ID: 7749408; Wakazono et al. 1995. PubMed ID: 7728148). Experimental studies suggest this variant impacts protein function (Fukao et al. 1995. PubMed ID: 7749408). A different amino acid substitution at this position (p.Thr297Lys) has been reported to be pathogenic (Su et al. 2017. PubMed ID: 28875337). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.