Submissions for variant NM_000019.4(ACAT1):c.935T>C (p.Ile312Thr)

gnomAD frequency: 0.00001  dbSNP: rs120074146

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pediatrics, Gifu University	RCV000002978	SCV000966096	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Invitae	RCV000002978	SCV001586092	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 312 of the ACAT1 protein (p.Ile312Thr). This variant is present in population databases (rs120074146, gnomAD 0.01%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9744475, 14518824, 25559898). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2844). 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: 9744475). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002978	SCV002598725	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2022-09-07	criteria provided, single submitter	clinical testing	Variant summary: ACAT1 c.935T>C (p.Ile312Thr) results in a non-conservative amino acid change located in the Thiolase, C-terminal domain (IPR020617) of 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 1.6e-05 in 250888 control chromosomes. c.935T>C has been reported in the literature as a biallelic compound heterozygous genotype in at-least two individuals affected with Alpha-Methylacetoacetic Aciduria with subsequent citations by others (example, Fukao_1998 cited in Fukao_2001). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Fukao_1998). The most pronounced variant effect results in <10% of normal Mitochondrial acetoacetyl-CoA thiolase (T2 enzyme) activity. 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000002978	SCV002794450	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2022-01-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002978	SCV004212883	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-08-07	criteria provided, single submitter	clinical testing
OMIM	RCV000002978	SCV000023136	pathogenic	Deficiency of acetyl-CoA acetyltransferase	1998-01-01	no assertion criteria provided	literature only