ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.890_892AGA[2] (p.Lys299del) (rs387906252)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000077926 SCV000883335 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing The ACADVL c.896_898delAGA; p.Lys299del variant (rs398123094) has been described in an individual identified by newborn screening and in an individual described as having very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Schiff 2013, Souri 1996). This variant is reported in ClinVar (Variation ID: 92292), and is found in the general population with an overall allele frequency of 0.02% (3/12518 alleles) in the Exome Variant Server. This variant deletes a single lysine residue leaving the rest of the protein in-frame. The lysine at codon 299 is conserved across mammals and the loss of this codon has been shown to result in an unstable transcript (Souri 1996). Based on available information, this variant is considered to be pathogenic. REFERENCES Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. 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.
Counsyl RCV000001694 SCV000220685 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-09-10 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077926 SCV000224740 pathogenic not provided 2013-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000077926 SCV000321373 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing The c.896_898delAGA variant in the ACADVL gene has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Souri et al., 1996). The deletion causes the loss of a single Lysine residue at amino acid position 299, denoted p.Lys299del. Analysis of the c.896_898delAGA variant in CHO cells found that the resultant mRNA and protein were unstable, that the resultant protein appeared abnormal in dimer assembly and was associated with undetectable activity of the VLCAD enzyme (Souri et al., 1996). The c.896_898delAGA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.896_898delAGA to be a pathogenic variant.
Invitae RCV000001694 SCV000654974 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-10-29 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 10 of the ACADVL mRNA (c.896_898delAGA). This leads to the deletion of 1 amino acid residue in the ACADVL protein (p.Lys299del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761162357, ExAC 0.01%). This variant has been reported as heterozygous in individuals with suspected VLCAD deficiency (PMID: 23480858, 8554073). ClinVar contains an entry for this variant (Variation ID: 92292). Experimental studies have shown that this deletion affects protein stability and activity in vitro (PMID: 8554073). 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.
OMIM RCV000001694 SCV000021850 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1996-01-01 no assertion criteria provided literature only

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