ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: rs28940872
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185700 SCV000238621 pathogenic not provided 2023-01-06 criteria provided, single submitter clinical testing Published functional studies demonstrate severely impaired folding and higher degradation rate compared to wildtype, supporting a damaging effect (Pedersen et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25670805, 26990548, 9499414, 28532786, 18523805, 22241096, 16926354, 11134486, 23798014, 30035407, 31980526, 14506246, 34426522, 31589614, 31813752, 33726816, 32778825, 27535533)
Invitae RCV000004033 SCV000632500 pathogenic Deficiency of butyryl-CoA dehydrogenase 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 383 of the ACADS protein (p.Arg383Cys). This variant is present in population databases (rs28940872, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-CoA dehydrogenase deficiency (PMID: 11134486, 16926354, 22241096, 30035407, 31813752; Invitae). This variant is also known as R359C. ClinVar contains an entry for this variant (Variation ID: 3829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9499414, 14506246, 18523805). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
Genome-Nilou Lab RCV000004033 SCV002033283 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-11-07 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000004033 SCV002768745 pathogenic Deficiency of butyryl-CoA dehydrogenase 2020-05-25 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_000017.3(ACADS):c.1147C>T in exon 10 of 10 of the ACADS gene. This substitution is predicted to create a major amino acid change from arginine to cysteine at position 383 of the protein, NP_000008.1 (ACADS):p.(Arg383Cys). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the Acyl-CoA dehydrogenase C-term domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.009% (26 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in patients with deficiency of short-chain acyl-CoA dehydrogenase (ClinVar; Gregersen, N. et al. (1998); Pedersen, C.B. et al. (2008); Corydon, M.J. et al. (2001); Waisbren, S.E. et al. (2013); Pena, L. et al. (2012)). In addition, studies show that this variant impacts protein function (Pedersen, C.B. et al. (2008); Gregersen, N. et al. (1998)). A different variant in the same codon resulting in a change to histidine has been reported VUS (ClinVar; Gregersen, N. et al. (2008)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Fulgent Genetics, Fulgent Genetics RCV000004033 SCV002800611 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2022-02-10 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000004033 SCV004176645 pathogenic Deficiency of butyryl-CoA dehydrogenase 2023-02-14 criteria provided, single submitter clinical testing
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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