ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1843C>T (p.Arg615Ter) (rs1057520507)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438504 SCV000515758 pathogenic not provided 2015-04-27 criteria provided, single submitter clinical testing The R615X nonsense variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency in a patient who was compound heterozygous for R615X and a relatively common 3-bp deletion of the ACADVL gene (Hahn et al., 1999). This variant is predicted to cause loss of normal protein function through protein truncation. Therefore, we consider R615X to be a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000438504 SCV000602381 pathogenic not provided 2017-12-04 criteria provided, single submitter clinical testing The ACADVL c.1843C>T; p.Arg615Ter variant occurs in the final coding exon and induces an early termination codon, most likely resulting in a truncated protein missing the last 40 amino acids, but could alternatively result in an absent transcript. The carboxy-terminal portion of the protein is thought to play an important role in mediating binding to the inner mitochondrial membrane (Goetzman 2007, Souri 1998, Wang 2010). Also, substitution of p.Arg615 (also known as R575) has been reported multiple times in association with VLCAD deficiency (Gobin-Limballe 2007, Hoffmann 2012, Mathur 1999, Miller 2015) and several other frameshifts and termination variants in this exon have been reported to be deleterious (Gobin-Limballe 2010, Miller 2015), thus providing additional support that the amino acids encoded by the final exon are functionally important. The p.Arg615Ter variant has been reported in individuals with VLCAD deficiency that were compound heterozygous with another ACADVL variant (Bu 2016, Hahn 1999). This variant has been reported to the ClinVar variant database (Variation ID: 379145), and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database). Taken together, this variant is considered pathogenic. References: Link to ClinVar database for p.Arg615Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/379145/ Bu Q et al. A Novel Missense Mutation in Very Long-chain Acyl-CoA Dehydrogenase Deficiency. Indian Pediatr. 2016 Mar;53(3):262. 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. 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 Dec;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 Jun;91(2):138-47. Hahn SH et al. Very long chain acyl coenzyme A dehydrogenase deficiency in a 5-month-old Korean boy: identification of a novel mutation. J Pediatr. 1999 Aug;135(2 Pt 1):250-3. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999 Mar 16;99(10):1337-43. 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. Souri M et al. Relationship between structure and substrate-chain-length specificity of mitochondrial very-long-chain acyl-coenzyme A dehydrogenase. Eur J Biochem. 1998 Nov 1;257(3):592-8. Wang Y et al. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem. 2010 Sep 24;285(39):29834-41.
Invitae RCV000537328 SCV000654945 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-04-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the ACADVL mRNA at codon 615 (p.Arg615*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 41 amino acids of the ACADVL protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the compound heterozygous state, co-occurring on the opposite chromosome with a known pathogenic ACADVL variant (PMID: 10431122). A different truncation downstream of this variant (p.Ala640fs*39) has been determined to be pathogenic (PMID: 17999356, 20060901). This suggests that deletion of this region of the ACADVL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000537328 SCV000916406 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-05 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1843C>T (p.Arg615X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 276976 control chromosomes (gnomAD). c.1843C>T has been reported in the literature in compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hahn 1999, Bu 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as Pathogenic.

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