ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs1305448140
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pediatrics, Gifu University RCV000844765 SCV000966029 pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000844765 SCV002242456 pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-05-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects ACAT1 function (PMID: 12754704). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 666460). Disruption of the initiator codon has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 12754704, 28220263). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the ACAT1 mRNA. The next in-frame methionine is located at codon 91.
Neuberg Centre For Genomic Medicine, NCGM RCV000844765 SCV004101482 pathogenic Deficiency of acetyl-CoA acetyltransferase criteria provided, single submitter clinical testing The initiator codon variant p.M1V in ACAT1 (NM_000019.4) has been previously reported in individuals affected with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency (Abdelkreem et al, 2019; Nguyen et al, 2017). The variant is reported to have reduced translational efficiency (11%) (Fukao, Matsuo, et al, 2003). The p.M1V variant is has a gnomAD frequency of 0.0006620 %. The p.M1V variant is a loss of function variant in the gene ACAT1, which is intolerant of Loss of Function variants. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The nucleotide change in ACAT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.The observed variant has also been detected in the spouse in heterozygous state.
Fulgent Genetics, Fulgent Genetics RCV000844765 SCV005680506 pathogenic Deficiency of acetyl-CoA acetyltransferase 2024-05-11 criteria provided, single submitter clinical testing

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