ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 352 of the ACADVL protein (p.Met352Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of VLCAD deficiency (PMID: 9973285, 35193651). This variant is also known as M312V. 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 with a positive predictive value of 95%. This variant disrupts the p.Met352 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32710939, 35193651). 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.

A Homozygous missense variation in exon 10 of the ACADVL gene that results in the amino acid substitution of Valine for Methionine at codon 352 was detected. The observed variant c.1054A>G (p.Met352Val) has not been reported in the 1000 genomes, gnomAD (v2.1) and topmed databases and has a minor allele frequency of 0.001% in the gnomAD (v3.1) database. The in silico prediction of the variant are damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

Variant summary: ACADVL c.1054A>G (p.Met352Val) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250952 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1054A>G has been reported in the literature in an unknown or presumed compound heterozygous state in at least 2 individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Andresen_1999, Huang_2022), including in at least 1 individual undergoing newborn screening. These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 9973285, 35193651). ClinVar contains an entry for this variant (Variation ID: 2851878). Based on the evidence outlined above, the variant was classified as uncertain significance.