ClinVar Genomic variation as it relates to human health

The K382N variant in the ACADVL gene has previously been reproted in a single individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency who was also compound heterozygous for a frameshift variant in the ACADVL gene (Ndukwe et al., 2013). The K382N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K382N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

The NM_000018.3:c.1146G>C (NP_000009.1:p.Lys382Asn) [GRCH38: NC_000017.11:g.7223201G>C] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys382 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8554073, 20060901, 29552494, 31497477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 389672). This missense change has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase deficiency (PMID: 23867825, 31031081). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 382 of the ACADVL protein (p.Lys382Asn). This variant is not present in population databases (gnomAD no frequency).

Variant summary: ACADVL c.1146G>C (p.Lys382Asn) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes. c.1146G>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example: Rovelli_2019). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Erlingsson_2014). The following publications have been ascertained in the context of this evaluation (PMID: 23867825, 27209629, 31031081). ClinVar contains an entry for this variant (Variation ID: 389672). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.