ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1376G>A (p.Arg459Gln) (rs751995154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185726 SCV000883346 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414939 SCV000492896 likely pathogenic Muscular Diseases; Rhabdomyolysis 2015-01-23 criteria provided, single submitter clinical testing
Counsyl RCV000412089 SCV000487128 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-10-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000412089 SCV000894149 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000185726 SCV000238652 pathogenic not provided 2017-07-19 criteria provided, single submitter clinical testing The R459Qmissense variant in the ACADVL gene has been reported previously in multiple patients with VLCADdeficiency (Spiekerkoetter et al., 2003; Laforet et al. 2009; McGoey et al. 2011; Miller et al. 2015).R459Q is a semi-conservative amino acid substitution, it occurs at a position that is conserved acrossspecies, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. In summary, we interpret R459Q to be pathogenic.
Invitae RCV000412089 SCV000654932 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 459 of the ACADVL protein (p.Arg459Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs751995154, ExAC 0.006%). This variant has been reported in individuals affected with VLCAD deficiency, the majority of them being clinically asymptomatic (PMID: 14517516, 23798014, 21429517). Only two symptomatic cases have been reported (PMID: 19327992, 23798014). This variant is also known as p.Arg419Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 203585). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that has been reported in symptomatic and asymptomatic individuals affected with VLCAD deficiency. This evidence indicates that the variant is pathogenic, but additional genetic or function data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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