Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pediatrics, |
RCV000844798 | SCV000966074 | likely pathogenic | Deficiency of acetyl-CoA acetyltransferase | 2019-05-05 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV000844798 | SCV004296135 | likely pathogenic | Deficiency of acetyl-CoA acetyltransferase | 2023-10-26 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 219 of the ACAT1 protein (p.Tyr219His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with ACAT1-related conditions (PMID: 17236799; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 666492). 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: 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. |
| Baylor Genetics | RCV000844798 | SCV005059106 | likely pathogenic | Deficiency of acetyl-CoA acetyltransferase | 2023-11-14 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000844798 | SCV005423522 | likely pathogenic | Deficiency of acetyl-CoA acetyltransferase | 2024-10-02 | criteria provided, single submitter | clinical testing | Variant summary: ACAT1 c.655T>C (p.Tyr219His) results in a conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) of the encoded protein sequence. Four 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 251310 control chromosomes. c.655T>C has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with acetoacetyl-CoA thiolase (T2) deficiency (example, Sakurai_2007). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in fibroblasts (example, Sakurai_2007). The following publication has been ascertained in the context of this evaluation (PMID: 17236799). ClinVar contains an entry for this variant (Variation ID: 666492). Based on the evidence outlined above, the variant was classified as likely pathogenic. |