ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1388G>A (p.Gly463Glu) (rs200366828)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522607 SCV000616634 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The G463E variant has previously been reported, as G423E, in two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al., 1999). The G463E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G463E 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the G463E variant is located within the substrate-binding pocket of VLCAD enzyme, where other missense variants in nearby residues have also been reported in association with VLCAD deficiency (McAndrew et al., 2008). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000809103 SCV000883347 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-12-31 criteria provided, single submitter clinical testing The ACADVL c.1388G>A; p.Gly463Glu variant (rs200366828), also known as Gly423Glu, has been reported in multiple unrelated individuals with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen 1999, Miller 2015). This variant is found on only seven chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 463 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, structural analyses indicate that this variant occurs within the substrate binding pocket directly adjacent to a residue involved in catalysis. Based on the available information, the p.Gly463Glu variant is considered to be likely pathogenic. References: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. 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.
Invitae RCV000809103 SCV000949243 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-06-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 463 of the ACADVL protein (p.Gly463Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs200366828, ExAC 0.005%). This variant has been observed in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). ClinVar contains an entry for this variant (Variation ID: 448982). 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000809103 SCV001364929 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1388G>A (NP_000009.1:p.Gly463Glu) [GRCH38: NC_000017.11:g.7224023G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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