ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.623G>A (p.Arg208Gln)

gnomAD frequency: 0.00004  dbSNP: rs370720208
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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 RCV000844797 SCV000966071 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000844797 SCV002301889 pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 208 of the ACAT1 protein (p.Arg208Gln). This variant is present in population databases (rs370720208, gnomAD 0.003%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 17236799; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198381). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 17236799). This variant disrupts the p.Arg208 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been observed in individuals with ACAT1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000844797 SCV004212783 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2023-11-18 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000179698 SCV000231988 uncertain significance not provided 2014-09-22 flagged submission clinical testing
PreventionGenetics, part of Exact Sciences RCV004754335 SCV005349054 likely pathogenic ACAT1-related disorder 2024-09-13 no assertion criteria provided clinical testing The ACAT1 c.623G>A variant is predicted to result in the amino acid substitution p.Arg208Gln. This variant has been reported in the compound heterozygous state in an individual with acetoacetyl-CoA thiolase deficiency (Sakurai et al. 2007. PubMed ID: 17236799). An in vitro functional study shows this variant impacts protein function (Sakurai et al. 2007. PubMed ID: 17236799). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

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