ClinVar Miner

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

gnomAD frequency: 0.00001
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020073 SCV000220281 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-04-30 criteria provided, single submitter literature only
Invitae RCV000020073 SCV000817229 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the ACADVL protein (p.Arg469Trp). This variant is present in population databases (rs113994170, gnomAD 0.01%). This missense change has been observed in individual(s) with very–long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 17999356, 27246109). This variant is also known as R429W. ClinVar contains an entry for this variant (Variation ID: 21017). 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. Experimental studies have shown that this missense change affects ACADVL function (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000020073 SCV000884950 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-04-16 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000020073 SCV001364930 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1405C>T (NP_000009.1:p.Arg469Trp) [GRCH38: NC_000017.11:g.7224040C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000020073 SCV001571362 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-04-13 criteria provided, single submitter clinical testing
Natera, Inc. RCV000020073 SCV002088794 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-04-21 no assertion criteria provided clinical testing

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