ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met) (rs113994169)

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
Invitae RCV000020069 SCV000654921 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 409 of the ACADVL protein (p.Thr409Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs113994169, ExAC 0.02%). This variant has been identified in multiple asymptomatic Hawaiian newborns (PMID: 24503138) and Maori and Pacific Islander newborns in New Zealand with abnormal newborn screening for VLCAD deficiency (PMID: 25085675). Of the 6 asymptomatic Hawaiian newborns that were homozygous for this variant, the majority had normal confirmatory plasma acylcarnitne analysis (PMID: 24503138). Fatty acid oxidation probe analysis was normal in New Zealand newborns that were homozygous for this variant but newborns who were compound heterozygous for this variant and a pathogenic variant had mild fatty acid oxidation impairment at 41 degrees centigrade (PMID: 25085675, abstract P-035). In addition, retrospective review of newborn screening cases of individuals that were below the NZ C14:1 cutoff but above the R4S cutoff (0.9 - 2.4μmol/L), showed that this variant is prevalent in the Maori population and was significantly associated with NBS C14:1 levels in this range but did not appear to be associated with increased prevalence of VLCADD clinical symptoms. ClinVar contains an entry for this variant (Variation ID: 21013). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a prevalent missense change in the Maori and Pacific Islander populations that is associated with a mild biochemical defect on newborn screening but most often normal confirmatory biochemical analysis. In the absence of additional functional and clinical data, this change has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755779 SCV000883345 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing
GeneReviews RCV000020069 SCV000040367 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to 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.