ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.473A>G (p.Asn158Ser) (rs199524907)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723373 SCV000231453 pathogenic not provided 2014-11-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179237 SCV000693970 pathogenic Deficiency of acetyl-CoA acetyltransferase 2020-06-11 criteria provided, single submitter clinical testing Variant summary: ACAT1 c.473A>G (p.Asn158Ser) results in a conservative amino acid change located in the Thiolase, N-terminal of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251402 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACAT1 causing Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (0.00031 vs 0.0029), allowing no conclusion about variant significance. c.473A>G has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency and has been subsequently cited by others (example, Sakurai_2007, Sarafoglou_2011, Abdelkreem_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sakurai_2007). The most pronounced variant effect results in a loss of catalytic activity due to an inability to fold into a tetramer configuration essential for the tertiary structure. A different missense substitution (p.Asn158Asp) at this location has been reported in patients with this disorder further corroborating a critical role of the Aspargine residue for protein function. 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=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000179237 SCV000819626 pathogenic Deficiency of acetyl-CoA acetyltransferase 2020-09-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 158 of the ACAT1 protein (p.Asn158Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199524907, ExAC 0.3%). This variant has been reported in individuals affected with acetoacetyl-CoA-thiolase deficiency (PMID: 17236799, 21669895). ClinVar contains an entry for this variant (Variation ID: 198030). Experimental studies have shown that this missense change abolishes acetyl-CoA thiolase activity in vitro (PMID: 17236799, 21669895). A different missense substitution at this codon (p.Asn158Asp) has been determined to be likely pathogenic (PMID: 17236799, 7749408, 27748876). This suggests that the asparagine residue is critical for ACAT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Gifu University RCV000179237 SCV000966063 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
GeneDx RCV000723373 SCV001780082 pathogenic not provided 2020-08-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Published functional studies demonstrate that N158S was associated with temperature sensitive instability, with faint to no detection of mutant protein at different temperatures as compared to wild-type protein (Sakurai et al., 2007).; This variant is associated with the following publications: (PMID: 31268215, 17236799, 21669895)

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.