ClinVar Miner

Submissions for variant NM_001609.3(ACADSB):c.1159G>A (p.Glu387Lys) (rs188094280)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000009781 SCV000361256 uncertain significance Deficiency of 2-methylbutyryl-CoA dehydrogenase 2017-09-08 criteria provided, single submitter clinical testing The ACADSB c.1159G>A (p.Glu387Lys) missense variant has been reported in two studies in which is it found in a homozygous state in one individual with acyl-CoA dehydrogenase, short/branched chain deficiency and in a compound heterozygous state in three individuals with no apparent clinical significance (Sass et al. 2008; Alfardan et al. 2010). The p.Glu387Lys variant is reported in four of 242 control chromosomes and at a frequency of 0.00061 in the Latino population of the Exome Aggregation Consortium. In vitro studies using patient fibroblasts demonstrated that the p.Glu387Lys variant impaired isoleucine degradation (Sass et al. 2008). Introduction of the variant into a prokaryotic expression vector showed no detectable protein on Western blotting, significantly reduced enzymatic activity to 2% of wild type and defects in protein folding and stability (Alfardan et al. 2010). Based on the evidence, the p.Glu387Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity 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 RCV000009781 SCV000934644 pathogenic Deficiency of 2-methylbutyryl-CoA dehydrogenase 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 387 of the ACADSB protein (p.Glu387Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs188094280, ExAC 0.06%). This variant has been observed in individuals with 2-methylbutyryl-coenzyme A dehydrogenase deficiency (PMID: 17945527, 20547083, Invitae). ClinVar contains an entry for this variant (Variation ID: 9203). An experimental study has shown that the protein with this missense change has 2% of wild-type protein activity in vitro (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091421 SCV001247459 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
OMIM RCV000009781 SCV000030002 pathogenic Deficiency of 2-methylbutyryl-CoA dehydrogenase 2008-01-01 no assertion criteria provided literature only

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