ClinVar Miner

Submissions for variant NM_000019.4(ACAT1):c.444_445del (p.Met148fs) (rs727503795)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000152743 SCV000231454 pathogenic not provided 2013-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000152743 SCV000490393 pathogenic not provided 2017-05-16 criteria provided, single submitter clinical testing The c.444_445delGG variant is not observed at a significant frequency in large population cohorts(Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thec.444_445delGG pathogenic variant in the ACAT1 gene causes a frameshift starting with codonMethionine 148, changes this amino acid to a Isoleucine residue and creates a premature Stop codon atposition 28 of the new reading frame, denoted p.Met148IlefsX28. This pathogenic variant is predictedto cause loss of normal protein function either through protein truncation or nonsense-mediatedmRNA decay. Although this variant has not been previously reported to our knowledge, it isinterpreted to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000179238 SCV000693969 likely pathogenic Deficiency of acetyl-CoA acetyltransferase 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The ACAT1 c.444_445delGG (p.Met148Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent ACAT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC in 1/121412 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACAT1 variant (0.0028868). This variant was found in one heterozygote individual through a carrier screening test with no additional information provided (Tanner_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000179238 SCV000829085 pathogenic Deficiency of acetyl-CoA acetyltransferase 2018-05-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met148Ilefs*28) in the ACAT1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727503795, ExAC 0.009%). This variant has been observed in an individual with beta-ketothiolase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 166649). Loss-of-function variants in ACAT1 are known to be pathogenic (PMID: 7749408). For these reasons, this variant has been classified as Pathogenic.

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