ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1531C>T (p.Arg511Trp) (rs771025937)

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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 RCV001000161 SCV001156649 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-02-25 criteria provided, single submitter clinical testing The c.1531C>T; p.Arg511Trp variant (rs771025937) has been reported in patients with symptoms suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Miller 2015). It is observed in the general population at a low overall frequency of 0.004% (10/250988 alleles) in the Genome Aggregation Database. The arginine is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. 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. 2007; Am J Hum Genet. 81(6):1133-43. Miller M 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. 2015;Mol Genet Metab. 116(3):139-45.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001000161 SCV001364934 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1531C>T (NP_000009.1:p.Arg511Trp) [GRCH38: NC_000017.11:g.7224242C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 17999356. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV001000161 SCV001416182 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 511 of the ACADVL protein (p.Arg511Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs771025937, ExAC 0.02%). This variant has been observed in combination with another ACADVL variant in an individual affected with VLCAD deficiency (PMID: 17999356). 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 C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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