ClinVar Genomic variation as it relates to human health

Published in vivo expression analysis showed no residual enzyme activity (Fukao et al., 1995); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 7749408, 7728148, 27748876)

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 158 of the ACAT1 protein (p.Asn158Asp). This variant is present in population databases (rs148639841, gnomAD 0.01%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 7749408, 17236799, 27748876). ClinVar contains an entry for this variant (Variation ID: 92297). 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. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 17236799). This variant disrupts the p.Asn158 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17236799, 21669895). 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.

This variant is interpreted as Likely Pathogenic, for 3-ketothiolase deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/7728148).

Variant summary: ACAT1 c.472A>G (p.Asn158Asp) results in a conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) and at the dimer interface (Abdelkreem_2019) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACAT1 causing Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (6e-05 vs 0.0029), allowing no conclusion about variant significance. c.472A>G has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Fukao_1995, Sakurai_2007, Otsuka_2016, Wojcik_2017). These data indicate that the variant is likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in reduced activity (Fukao_1995, Wakazono_1995, Sakurai_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

The ACAT1 c.472A>G variant is predicted to result in the amino acid substitution p.Asn158Asp. This variant has been reported with a second pathogenic variant in four affected individuals (Fukao et al. 1995. PubMed ID: 7749408; Sakurai et al. 2007. PubMed ID: 17236799; Otsuka et al. 2016. PubMed ID: 27748876). In vitro functional studies found the p.Asn158Asp substitution resulted in a protein with no residual activity (Fukao et al. 1995. PubMed ID: 7749408; Sakurai et al. 2007. PubMed ID: 17236799). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.