Variant summary: ACAT1 c.444_445delGG (p.Met148IlefsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251452 control chromosomes. c.444_445delGG has been reported in the literature in one heterozygote individual evaluated on a pan-ethnic carrier screening assay with no additional information provided (example, Tanner_2014). This report does not provide unequivocal conclusions about the phenotypic association of the variant in an individual affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency. Although based on loss of function as an established mechanism of disease in individuals with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency, this variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously reported as pathogenic or benign in an affected individual to our knowledge; This variant is associated with the following publications: (PMID: 24517888)

This sequence change creates a premature translational stop signal (p.Met148Ilefs*28) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs727503795, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with beta-ketothiolase deficiency (internal data). ClinVar contains an entry for this variant (Variation ID: 166649). For these reasons, this variant has been classified as Pathogenic.