ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.444_445del (p.Met148fs) (rs727503795)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000152743 SCV000231454 pathogenic not provided 2013-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000152743 SCV000490393 pathogenic not provided 2017-05-16 criteria provided, single submitter clinical testing The c.444_445delGG variant is not observed at a significant frequency in large population cohorts(Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thec.444_445delGG pathogenic variant in the ACAT1 gene causes a frameshift starting with codonMethionine 148, changes this amino acid to a Isoleucine residue and creates a premature Stop codon atposition 28 of the new reading frame, denoted p.Met148IlefsX28. This pathogenic variant is predictedto cause loss of normal protein function either through protein truncation or nonsense-mediatedmRNA decay. Although this variant has not been previously reported to our knowledge, it isinterpreted to be a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179238 SCV000693969 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2021-04-17 criteria provided, single submitter clinical testing 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.
Invitae RCV000179238 SCV000829085 pathogenic Deficiency of acetyl-CoA acetyltransferase 2020-07-09 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs727503795, ExAC 0.009%). This variant has been observed in an individual with beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 166649). Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.