Submissions for variant NM_000019.4(ACAT1):c.826+1G>T

gnomAD frequency: 0.00001  dbSNP: rs727503796

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790759	SCV000232458	pathogenic	not provided	2013-12-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180090	SCV000828395	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2023-01-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 1346617). ClinVar contains an entry for this variant (Variation ID: 166650). This variant is also known as IVS8+1g>t. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617, 15128923; Invitae). This variant is present in population databases (rs727503796, gnomAD 0.002%). This sequence change affects a donor splice site in intron 8 of the ACAT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180090	SCV000918385	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2018-11-01	criteria provided, single submitter	clinical testing	Variant summary: ACAT1 c.826+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions are supported by several publications that report experimental evidence showing exon 8 skipping (Fukao_1992) and absent enzyme activity and protein expression (Zhang_2004). The variant allele was found at a frequency of 8.2e-06 in 245060 control chromosomes (gnomAD). The variant, c.826+1G>T, has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency as both a homozygous and compound heterozygous allele (Fukao_1992, Grunert_2017, Zhang_2004). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Pediatrics, Gifu University	RCV000180090	SCV000966086	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2019-05-05	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000180090	SCV002785321	likely pathogenic	Deficiency of acetyl-CoA acetyltransferase	2021-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000180090	SCV004217090	pathogenic	Deficiency of acetyl-CoA acetyltransferase	2022-05-13	criteria provided, single submitter	clinical testing
OMIM	RCV000180090	SCV000023126	pathogenic	Deficiency of acetyl-CoA acetyltransferase	1992-02-01	no assertion criteria provided	literature only