ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1878G>A (p.Trp626Ter) (rs1555529186)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000652044 SCV000773910 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-08-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ACADVL gene (p.Trp626*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acids of the ACADVL protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals who tested positive for very long chain acyl-coA dehydrogenase deficiency on newborn screening (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 541724). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000652044 SCV000883338 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-08-09 criteria provided, single submitter clinical testing The ACADVL c.1878G>A; p.Trp626Ter variant is reported in the medical literature in at least one individual sent for newborn screening of very-long-chain acyl-CoA dehydrogenase deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 541724), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a premature termination codon and truncates the terminal 30 amino acids. These amino acids are unique amongst acyl-CoA dehydrogenases, but have no reported critical function (Goetzman 2007, McAndrew 2008). Due to limited information, the clinical significance of the p.Trp626Ter variant is uncertain at this time. References: Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000652044 SCV001364944 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1878G>A (NP_000009.1:p.Trp626Ter) [GRCH38: NC_000017.11:g.7225007G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 26385305. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

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