ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185723 SCV000238649 pathogenic not provided 2021-01-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Expression of G439D in E. coli found no detectable enzyme activity compared to wild-type controls (Schiff et al., 2013); This variant is associated with the following publications: (PMID: 30925787, 23169530, 27209629, 17999356, 23480858, 30194637, 31031081, 20060901)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185723 SCV000700260 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing
Invitae RCV000703664 SCV000832574 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-02 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, Invitae). ClinVar contains an entry for this variant (Variation ID: 203582). This variant has been reported to affect ACADVL protein function (PMID: 23480858). This variant disrupts the p.Gly amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000703664 SCV001364919 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1316G>A (NP_000009.1:p.Gly439Asp) [GRCH38: NC_000017.11:g.7223859G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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