ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1882del (p.Gln628fs) (rs1597541142)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001435 SCV001158672 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-03-21 criteria provided, single submitter clinical testing The ACADVL c.1882delC; p.Gln628fs variant (rs371091547), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a frameshift in the last exon of the ACADVL gene. While this may not lead to nonsense-mediated decay, it is expected to create a protein that would include a sequence of 52 amino acid residues in place of the final 28 canonical amino acids. Supporting the notion that this variant is deleterious, frameshift variants downstream of the p.Gln628fs variant have been reported in individuals with VLCAD deficiency and are considered pathogenic (Gobin-Limballe 2010, Miller 2015). Based on available information, the p.Gln628fs variant is considered to be likely pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Miller MJ 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. Mol Genet Metab. 2015 Nov;116(3):139-45.
Invitae RCV001001435 SCV001215529 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-02-21 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the ACADVL gene (p.Gln628Lysfs*52). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acids of the ACADVL protein and extend the protein by an additional 23 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ACADVL variant in an individual with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant results in an extension of the ACADVL protein. Other variant(s) that result in a similarly extended protein product (p.Ala640Trpfs*39) have been observed in individuals with ACADVL-related conditions (PMID: 17999356). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001001435 SCV001361317 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-06-02 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1882delC (p.Gln628LysfsX52) causes a frameshift which results in an extension of the protein. The variant was absent in 251310 control chromosomes. To our knowledge, no occurrence of c.1882delC in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, other variants causing an extension of the protein have been reported as pathogenic in ClinVar and HGMD. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.