ClinVar Miner

Submissions for variant NM_014384.2(ACAD8):c.988C>T (p.Arg330Trp) (rs121908420)

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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 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.
Invitae RCV000005688 SCV000812492 uncertain significance Deficiency of isobutyryl-CoA dehydrogenase 2018-06-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 330 of the ACAD8 protein (p.Arg330Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121908420, ExAC 0.009%). This variant has been observed as homozygous in an individual affected with isobutyryl-CoA dehydrogenase deficiency (PMID: 17304052). This variant is also known in the literature as R308W. ClinVar contains an entry for this variant (Variation ID: 5357). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000005688 SCV000025870 pathogenic Deficiency of isobutyryl-CoA dehydrogenase 2007-02-01 no assertion criteria provided literature only

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