ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.473A>G (p.Asn158Ser) (rs199524907)

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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 RCV000179237 SCV000966063 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2019-05-05 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723373 SCV000231453 pathogenic not provided 2014-11-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000179237 SCV000693970 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2017-08-07 criteria provided, single submitter clinical testing Variant summary: The ACAT1 c.473A>G (p.Asn158Ser) variant involves the alteration of a conserved nucleotide and is present at thiolase domain. 2/4 in silico tools predict a deleterious outcome. This variant was found in 33/121410 control chromosomes at a frequency of 0.0002718, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant has been reported in multiple MATD patients in compound heterozygousity with other mutation such as c.52dupC and N353K (Sakurai_2007, Sarafoglou_2011) in trans. In a family, two affected sibling carried this variant were compound heterozygous for the variant along with c.52dupC and their unaffected mother was heterozygous for this variant, suggesting that this variant cosegregated with disease in the family (Sarafoglou_2011). In a compound heterozygote, there was absence of T2 enzymatic activity, strongly supporting for pathogenicity (Sakurai_2007). Another missense variant at the same residue, p.Asn158Asp, has been reported as pathogenic by two labs in ClinVar as well as in a publication (Sakurai_2007), suggesting that missense variants are unlikely to be tolerated at this residue. In addition, one clinical diagnostic laboratory and a reputable database classify this variant as pathogenic. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
Invitae RCV000179237 SCV000819626 pathogenic Deficiency of acetyl-CoA acetyltransferase 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 158 of the ACAT1 protein (p.Asn158Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199524907, ExAC 0.3%). This variant has been reported in individuals affected with acetoacetyl-CoA-thiolase deficiency (PMID: 17236799, 21669895). ClinVar contains an entry for this variant (Variation ID: 198030). Experimental studies have shown that this missense change abolishes acetyl-CoA thiolase activity in vitro (PMID: 17236799, 21669895). A different missense substitution at this codon (p.Asn158Asp) has been determined to be likely pathogenic (PMID: 17236799, 7749408, 27748876). This suggests that the asparagine residue is critical for ACAT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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