ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.218A>C (p.Gln73Pro)

dbSNP: rs779758622
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pediatrics, Gifu University RCV000844774 SCV000966041 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
Invitae RCV000844774 SCV002286320 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-04-22 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 17236799). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change alters ACAT1 gene expression (PMID: 17236799). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACAT1 protein function. ClinVar contains an entry for this variant (Variation ID: 666469). This variant is present in population databases (rs779758622, gnomAD 0.002%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 73 of the ACAT1 protein (p.Gln73Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000844774 SCV003934537 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-05-03 criteria provided, single submitter clinical testing Variant summary: ACAT1 c.218A>C (p.Gln73Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. c.218A>C has been reported in the literature in individuals affected with Alpha-Methylacetoacetic Aciduria (Sakurai_2007). These data do not allow any conclusion about variant significance. One publication reports expression studies indicating absense of residual T2 protein and enzyme activity (Sakurai_2007) . The following publications have been ascertained in the context of this evaluation (PMID: 17236799). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000844774 SCV004214722 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-03-27 criteria provided, single submitter clinical testing

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