ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.1147C>T (p.Arg383Cys) (rs28940872)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185700 SCV000238621 pathogenic not provided 2018-10-31 criteria provided, single submitter clinical testing The R383C pathogenic variants has been reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency using an alternate numbering system based on the processed protein (Gregersen et al., 1998).
Invitae RCV000004033 SCV000632500 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 383 of the ACADS protein (p.Arg383Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28940872, ExAC 0.02%). This variant has been reported to be homozygous or in combination with another ACADS variant in individuals affected with short-chain acyl-CoA dehydrogenase deficiency (PMID: 22241096, 16926354, 11134486, 30035407). This variant is also known as R359C in the literature. ClinVar contains an entry for this variant (Variation ID: 3829). Experimental studies have shown that this missense change causes a significant reduction in ACADS enzyme activity and protein expression and no tetramer formation. This variant causes severe misfolding of the protein and no rapid protein degradation leading to the formation of insoluble protein aggregates (PMID: 18523805, 14506246, 9499414). For these reasons, this allele has been classified as Likely Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000004033 SCV000915578 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2018-12-17 criteria provided, single submitter clinical testing The ACADS c.1147C>T (p.Arg383Cys) missense variant has been reported in at least five studies and is found in a total of eight individuals with SCAD deficiency including in one in a homozygous state, four in a compound heterozygous state, and three in a heterozygous state (Gregersen et al. 1998; Corydon et al. 2001; Pedersen et al. 2008; Dessein et al. 2017; Kilic et al. 2017). All of the compound heterozygous individuals also carried a c.625G>A variant in a homozygous or heterozygous state. The p.Arg383Cys variant was absent from 248 healthy controls and is reported at a frequency of 0.000681 in the African American population of the Exome Sequencing Project. Pedersen et al. (2003) found thep.Arg383Cys variant caused severely impaired folding and exhibited an increased dependence on the hsp60 machinery and remained associated with the hsp60 complex for longer periods of time than wild type protein. Based on the evidence, the p.Arg383Cys variant is classified as likely pathogenic for SCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000004033 SCV000024199 pathogenic Deficiency of butyryl-CoA dehydrogenase 2001-01-01 no assertion criteria provided literature only
Counsyl RCV000004033 SCV000678045 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2017-03-14 no assertion criteria provided clinical testing

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