ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1838G>A (p.Arg613Gln) (rs534647044)

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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 RCV000756953 SCV000884954 likely pathogenic not provided 2017-10-27 criteria provided, single submitter clinical testing The ACADVL c.1838G>A; p.Arg613Gln variant is reported in the medical literature in an individual with very-long chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (Olpin 2017). Additionally, another variant in the same codon, p.Arg613Trp, is reported in individuals with VLCAD deficiency (Gobin-Limballe 2007, Laforet 2009, Souri 1996, Strauss 1996). The p.Arg613Gln variant is not reported in the ClinVar database, but is listed in the dbSNP variant database (rs534647044) and the Genome Aggregation Database in 5/276924 alleles. The arginine at this position is well conserved across species, is located in a functional domain, and is hypothesized to be involved in dimerization of the protein (Goetzman 2007). Considering available information, this variant is classified as likely pathogenic. References: Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007 81(6):1133-43. 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 91(2):138-47. Olpin SE et al. Fibroblast Fatty-Acid Oxidation Flux Assays Stratify Risk in Newborns with Presumptive-Positive Results on Screening for Very-Long Chain Acyl-CoA Dehydrogenase Deficiency. Int J Neonat Screen. 2017 3(1), 2. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. 2009 Neuromuscul Disord. 19(5):324-9. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 58(1):97-106. Strauss AW et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A. 1995 92(23):10496-500.
Invitae RCV001060887 SCV001225604 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 613 of the ACADVL protein (p.Arg613Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs534647044, ExAC 0.02%). This variant has been observed in combination with another ACADVL variant in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 30194637, ClinVar contains an entry for this variant (Variation ID: 618502). 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). This variant disrupts the p.Arg613 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17999356, 18670371, 23430950, 26881790, 28755359). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001060887 SCV001365134 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1838G>A (NP_000009.1:p.Arg613Gln) [GRCH38: NC_000017.11:g.7224967G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4

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