Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 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 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 613 of the ACADVL protein (p.Arg613Gln). This variant is present in population databases (rs534647044, gnomAD 0.008%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 30194637, 32710939; https://www.mdpi.com/2409-515X/3/1/2/htm). ClinVar contains an entry for this variant (Variation ID: 618502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic. |
| Wong Mito Lab, |
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 |
| Revvity Omics, |
RCV001060887 | SCV002021275 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2021-05-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001060887 | SCV002074384 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2022-01-21 | criteria provided, single submitter | clinical testing | Variant summary: ACADVL c.1838G>A (p.Arg613Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251108 control chromosomes. c.1838G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Olpin_2017, Miller_2015, Hesse_2018, Lin_2020, Guffon_2021, Olsson_2021). These data indicate that the variant is likely to be associated with disease. Enzyme activity of compound heterozygous patients cells were measured at <20% of wild-type (Olpin_2017, Olsson_2021). Additionally, a different variant affecting the same amino acid has been reported in association with VLCAD (R613W). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV001060887 | SCV004215103 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-08-01 | criteria provided, single submitter | clinical testing |