ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.1034A>T (p.Asp345Val) (rs771978135)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543549 SCV000630274 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-04-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 345 of the ACADM protein (p.Asp345Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs771978135, ExAC 0.009%) but has not been reported in the literature in individuals with a ACADM-related disease. However, a different Variant of Uncertain Significance affecting the same codon (p.Asp345Tyr) has been reported in an individual affected with MCAD deficiency (PMID: 23028790) and has been shown to disrupt protein function in vitro (PMID: 24966162). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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