ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs727503796
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Total submissions: 7
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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
Invitae 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

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