ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.826+1G>T (rs727503796)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pediatrics, Gifu University RCV000180090 SCV000966086 pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790759 SCV000232458 pathogenic not provided 2013-12-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000180090 SCV000828395 pathogenic Deficiency of acetyl-CoA acetyltransferase 2018-05-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the ACAT1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with other ACAT1 variants in individuals with beta-ketothiolase deficiency (PMID: 1346617, Invitae). ClinVar contains an entry for this variant (Variation ID: 166650). Experimental studies have shown that this splice donor change causes exon 8 skipping (PMID: 1346617). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000180090 SCV000023126 pathogenic Deficiency of acetyl-CoA acetyltransferase 1992-02-01 no assertion criteria provided literature only

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