ClinVar Genomic variation as it relates to human health

Variant summary: ACAT1 c.433C>G (p.Gln145Glu) results in a conservative amino acid change located in the N-terminal domain (IPR020616) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant disrupts the third to last nucleotide of exon 5, and therefore can affect splicing. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251110 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.433C>G has been reported in the literature in at least one homozygous individual affected with Alpha-Methylacetoacetic Aciduria (e.g., Fukao_2001, Fukao_2002). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant protein displayed increased thermal instability resulting in approximately 10-15% enzymatic activity at 37 degrees Celsius (e.g., Fukao_2001, Fukao_2002, Nakamura_2001). However, the variant protein was also found to maintain 100% specific activity in vitro (Fukao_2002). The following publications have been ascertained in the context of this evaluation (PMID: 11161836, 11914035, 11161837). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces glutamine with glutamic acid at codon 145 of the ACAT1 protein (p.Gln145Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs120074148, ExAC 0.009%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 11161836). ClinVar contains an entry for this variant (Variation ID: 2846). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ACAT1 function (PMID: 11914035). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.