ClinVar Miner

Submissions for variant NM_014384.3(ACAD8):c.988C>T (p.Arg330Trp)

gnomAD frequency: 0.00001  dbSNP: rs121908420
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000523989 SCV000341545 likely pathogenic not provided 2016-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000523989 SCV000616629 likely pathogenic not provided 2017-10-27 criteria provided, single submitter clinical testing The R330W variant in the ACAD8 gene has been reported previously in association with isobutyryl-CoA dehydrogenase deficiency in two unrelated individuals, one of which was reported in the homozygous state (as R308W due to alternate nomenclature) (Pedersen et al., 2006; Oglesbee et al., 2007). The R330W variant is not observed in the homozygous state or at a significant frequency in large population cohorts (Lek et al., 2016). The R330W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R330W as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000005688 SCV000812492 likely pathogenic Deficiency of isobutyryl-CoA dehydrogenase 2022-06-28 criteria provided, single submitter clinical testing 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. 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 ACAD8 protein function. ClinVar contains an entry for this variant (Variation ID: 5357). This missense change has been observed in individuals with isobutyryl-CoA dehydrogenase deficiency (PMID: 17304052; Invitae). This variant is present in population databases (rs121908420, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 330 of the ACAD8 protein (p.Arg330Trp).
Baylor Genetics RCV000005688 SCV001519947 uncertain significance Deficiency of isobutyryl-CoA dehydrogenase 2020-02-19 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV000005688 SCV003822430 uncertain significance Deficiency of isobutyryl-CoA dehydrogenase 2020-04-04 criteria provided, single submitter clinical testing
OMIM RCV000005688 SCV000025870 pathogenic Deficiency of isobutyryl-CoA dehydrogenase 2007-02-01 no assertion criteria provided literature only

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