ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.380C>T (p.Ala127Val)

gnomAD frequency: 0.00001  dbSNP: rs1591363760
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pediatrics, Gifu University RCV000844784 SCV000966052 pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
Invitae RCV000844784 SCV002266407 pathogenic Deficiency of acetyl-CoA acetyltransferase 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the ACAT1 protein (p.Ala127Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 11161837, 11914035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 666479). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 11914035). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 5 (PMID: 11161837). This variant disrupts a region of the ACAT1 protein in which other variant(s) (p.Cys126Ser) have been determined to be pathogenic (PMID: 31268215; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000844784 SCV004214578 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-07-10 criteria provided, single submitter clinical testing

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