ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.472A>G (p.Asn158Asp) (rs148639841)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077931 SCV000231451 pathogenic not provided 2013-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000077931 SCV000329851 pathogenic not provided 2017-08-04 criteria provided, single submitter clinical testing The N158D pathogenic variant in the ACAT1 gene has been reported previously in combination with other pathogenic variants in individuals with alpha-methylacetoacetic aciduria (Wakazono et al, 1995; Fukao et al., 1995). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000231451.1; Landrum et al., 2015). In vivo expression analysis of N158D showed no residual enzyme activity (Fukao et al., 1995). The N158D variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. We interpret N158D as a pathogenic variant.
SIB Swiss Institute of Bioinformatics RCV000179235 SCV000883254 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2018-10-15 criteria provided, single submitter curation 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).
Department of Pediatrics, Gifu University RCV000179235 SCV000966062 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
Invitae RCV000179235 SCV001221859 pathogenic Deficiency of acetyl-CoA acetyltransferase 2020-01-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 158 of the ACAT1 protein (p.Asn158Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs148639841, ExAC 0.01%). This variant has been observed in combination with another ACAT1 variant in several individuals affected with beta-ketothiolase deficiency (PMID: 27748876,17236799, 7749408). ClinVar contains an entry for this variant (Variation ID: 92297). This variant has been reported to affect ACAT1 protein function (PMID:17236799). This variant disrupts the p.Asn158 amino acid residue in ACAT1. Another variant that disrupts this residue has been observed in individuals with ACAT1-related conditions (PMID: 17236799, 21669895), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000179235 SCV001460761 pathogenic Deficiency of acetyl-CoA acetyltransferase 2020-09-16 no assertion criteria provided clinical testing

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