ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp) (rs533055438)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185723 SCV000884949 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing The ACADVL c.1316G>A; p.Gly439Asp variant (rs533055438) is reported in the literature in individuals diagnosed with VLCAD deficiency, who are heterozygous for another ACADVL variant (Gobin-Limballe 2010, Pena 2016, Schiff 2013). Cultured fibroblasts from an individual carrying p.Gly439Asp and p.Met443Arg, showed no detectable VLCAD activity (Schiff 2013). Furthermore, functional analysis of p.Gly439Asp expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by Western blot (Schiff 2013). The p.Gly439Asp variant is reported as pathogenic in ClinVar (Variation ID: 203582), and found in the general population with a low frequency of 0.002% (6/277134 alleles) in the Genome Aggregation Database. The glycine at codon 439 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Based on the above information, this variant is considered pathogenic. REFERENCES Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185723 SCV000700260 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000185723 SCV000238649 pathogenic not provided 2017-07-17 criteria provided, single submitter clinical testing The G439D pathogenic variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe et al., 2007; Schiff et al., 2013; Pena et al., 2016). Expression of G439D in e. coli found that enzyme activity associated with this variant was undetectable (Schiff et al., 2013). The G439D 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 G439D 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret G439D to be a pathogenic variant.
Invitae RCV000703664 SCV000832574 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 439 of the ACADVL protein (p.Gly439Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs533055438, ExAC 0.01%). This variant has been observed in combination with other ACADVL variants in several individuals affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 17999356, 23480858). ClinVar contains an entry for this variant (Variation ID: 203582). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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