Submissions for variant NM_000019.4(ACAT1):c.622C>T (p.Arg208Ter)

gnomAD frequency: 0.00002  dbSNP: rs532190594

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000434420	SCV000510705	pathogenic	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000689417	SCV000817065	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg208*) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). This variant is present in population databases (rs532190594, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with acetoacetyl-CoA-thiolase deficiency (PMID: 20156697, 28220263). It is commonly reported in individuals of Vietnamese ancestry (PMID: 20156697, 28220263). ClinVar contains an entry for this variant (Variation ID: 376832). For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Gifu University	RCV000689417	SCV000966070	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000689417	SCV002041661	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2021-11-21	criteria provided, single submitter	clinical testing	Variant summary: ACAT1 c.622C>T (p.Arg208X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251186 control chromosomes. c.622C>T has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (example, Nguyen_2017, Fukao_2010, Lin_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000689417	SCV004210497	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-09-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000689417	SCV001461795	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000689417	SCV004800856	pathogenic	Deficiency of acetyl-CoA acetyltransferase		no assertion criteria provided	clinical testing	PS3+PM2_P+PM3_S+PP4