ClinVar Miner

Submissions for variant NM_001609.3(ACADSB):c.443C>T (p.Thr148Ile) (rs58639322)

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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 RCV000389934 SCV000341243 uncertain significance not provided 2016-04-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000009780 SCV000915461 pathogenic Deficiency of 2-methylbutyryl-CoA dehydrogenase 2017-04-28 criteria provided, single submitter clinical testing The ACADSB c.443C>T (p.Thr148Ile) missense variant has been reported in at least three studies in which it is found in a total of six patients with acyl-CoA dehydrogenase, short/branched chain deficiency, including in three, of whom two are siblings, who carried the variant in a homozygous state, and three, of whom two are siblings, who carried the variant in a compound heterozygous state (Korman et al. 2005; Sass et al. 2008; Alfardan et al. 2010). The p.Thr148Ile variant was not detected in 92 control chromosomes and is reported at a frequency of 0.0023 in the South Asian population of the Exome Aggregation Consortium. In vitro expression in E. coli found that the p.Thr148Ile variant protein had almost undetectable activity compared to wild type (Alfardan et al. 2010). It should be noted that some individuals with this disorder may remain asymptomatic throughout life. Based on the evidence, the p.Thr148Ile variant is classified as pathogenic for acyl-CoA dehydrogenase, short/branched chain deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000009780 SCV000645153 likely pathogenic Deficiency of 2-methylbutyryl-CoA dehydrogenase 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 148 of the ACADSB protein (p.Thr148Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs58639322, ExAC 0.2%). This variant has been reported in several individuals affected with SBCAD deficiency (PMID: 15615815, 20547083, 17945527). ClinVar contains an entry for this variant (Variation ID: 9202). Experimental studies have shown that this missense change decreases ACADSB enzymatic activity to 2.8% of wild-type in vitro (PMID: 20547083). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000009780 SCV000030001 pathogenic Deficiency of 2-methylbutyryl-CoA dehydrogenase 2008-01-01 no assertion criteria provided literature only

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