ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp)

gnomAD frequency: 0.00001  dbSNP: rs766742117
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506090 SCV000602370 likely pathogenic not specified 2017-01-10 criteria provided, single submitter clinical testing
Invitae RCV000652041 SCV000773905 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-10-14 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 459 of the ACADVL protein (p.Arg459Trp). This variant is present in population databases (rs766742117, gnomAD 0.009%). This missense change has been observed in individual(s) with biochemical features of very long chain acyl-CoA dehydrogenase deficiency but in whom no second allele was reported (PMID: 9973285, 10738914, 21932095, 26385305; Invitae). ClinVar contains an entry for this variant (Variation ID: 203584). 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. This variant disrupts the p.Arg459 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14517516, 19327992, 21429517, 23798014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000652041 SCV001364926 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1375C>T (NP_000009.1:p.Arg459Trp) [GRCH38: NC_000017.11:g.7224010C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000506090 SCV002500789 uncertain significance not specified 2022-03-31 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1375C>T (p.Arg459Trp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1375C>T has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in heterozygous state. These reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000652041 SCV004213666 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-01-18 criteria provided, single submitter clinical testing

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