ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1837C>T (p.Arg613Trp) (rs118204014)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001690 SCV000220191 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-03-29 criteria provided, single submitter literature only
GeneDx RCV000185733 SCV000238660 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing The R613W missense mutation identified in the ACADVL gene has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Strauss et al., 1995). Functional studies have shown that the R613W mutation significantly impacts enzyme activity (Goetzman et al., 2007). The The variant is found in ACADVL panel(s).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000001690 SCV000602366 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-04-11 criteria provided, single submitter clinical testing The ACADVL c.1837C>T; p.Arg613Trp variant (rs118204014), also published as Arg573Trp, is reported in the literature in individuals affected with very-long chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Laforet 2009, Strauss 1995, Souri 1996). In multiple affected patients, this variant was observed in trans to a second pathogenic variant (Gobin-Limballe 2007, Strauss 1995, Souri 1996). This variant is found in the general population with an overall allele frequency of 0.005% (14/282476 alleles) in the Genome Aggregation Database, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1623). The arginine at codon 613 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. Additionally, several publications have shown that this variant results in reduced dimerization and enzyme function (Gobin-Limballe 2007, Goetzman 2007, Souri 1996). Taken together, the p.Arg613Trp variant is considered 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 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. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009 May;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 Jan;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 Nov 7;92(23):10496-500.
Invitae RCV000001690 SCV000821526 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 613 of the ACADVL protein (p.Arg613Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs118204014, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another ACADVL variant in individuals affected with very long chain acyl-CoA dehydrogenase (PMID: 10077518, 7479827, 19327992, 17999356, 8554073). ClinVar contains an entry for this variant (Variation ID: 1623). Experimental studies have shown that this missense change abrogates ACADVL enzyme activity in vitro (PMID: 17374501, 8554073). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000001690 SCV000914789 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-09-20 criteria provided, single submitter clinical testing The ACADVL c.1837C>T (p.Arg613Trp) variant has been reported in at least four studies and is found in a total of five probands with VLCAD deficiency including two in a homozygous state and three in a compound heterozygous state (Strauss et al. 1995; Gobin-Limballe et al. 2007; Laforet et al. 2009; Bouvier et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of proband fibroblasts reported by revealed significantly lower VLCAD enzyme activity and no detectable ACADVL protein (Hale et al. 1985; Strauss et al. 1995; Aoyama et al. 1995). Souri et al. (1996) reported the p.Arg613Trp variant protein expressed in CHO cells had significantly less protein accumulation when compared to wild type despite normal mRNA levels, reduced VLCAD activity, and failure to homodimerize. Further, Goetzman et al. (2007) used a bacterial expression system to confirm that the p.Arg613Trp variant protein has no VLCAD activity. Based on the evidence, the p.Arg613Trp variant is classified as pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000001690 SCV000021846 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1996-01-01 no assertion criteria provided literature only

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