ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp) (rs766742117)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506090 SCV000602370 likely pathogenic not specified 2017-01-10 criteria provided, single submitter clinical testing
Invitae RCV000652041 SCV000773905 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-08-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 459 of the ACADVL protein (p.Arg459Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs766742117, ExAC 0.01%). This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase deficiency but in whom no second allele was reported (PMID: 9973285, 21932095, 10738914). ClinVar contains an entry for this variant (Variation ID: 203584). 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. A different missense substitution at this codon (p.Arg459Gln) has been determined to be pathogenic (PMID: 19327992, 23798014, 14517516, 23798014, 21429517). This suggests that the arginine residue is critical for ACADVL protein function and that other missense substitutions at this position may also be pathogenic. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000652041 SCV001364926 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1375C>T (NP_000009.1:p.Arg459Trp) [GRCH38: NC_000017.11:g.7224010C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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