ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1405C>T (p.Arg469Trp) (rs113994170)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756952 SCV000884950 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing The ACADVL c.1405C>T; p.Arg469Trp variant (rs113994170), also known as Arg429Trp, has been reported in multiple individuals with VLCAD deficiency, including three severely affected individuals that were homozygous for the variant (Andresen 1999). Additionally, functional studies have shown that the variant protein has significantly reduced enzymatic activity (Goetzman 2007, Hoffmann 2012). This variant is reported in ClinVar (Variation ID: 21017), and observed in the general population with low overall allele frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.003 percent (7/246250 alleles, Genome Aggregation Database). The arginine at codon 469 is well conserved across species, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. 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. 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.
Counsyl RCV000020073 SCV000220281 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-04-30 criteria provided, single submitter literature only
GeneReviews RCV000020073 SCV000040371 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000020073 SCV000817229 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 469 of the ACADVL protein (p.Arg469Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs113994170, ExAC 0.003%). This variant has been reported as homozygous or in combination with another ACADVL variant in several individuals affected with very–long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 17999356, 27246109). This variant is also known as R429W in the literature. ClinVar contains an entry for this variant (Variation ID: 21017). An experimental study has shown that this missense change abolishes VLCAD enzymatic activity (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic.

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