The c.1372T>C variant is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 458 (p.Phe458Leu). This variant has also been published as Phe418Leu when numbered from the mature peptide. The c.1372T>C variant has been described in at least three individuals diagnosed with very long chain acyl CoA dehydrogenase (VLCAD), with at least two also carrying an additional pathogenic or likely pathogenic ACADVL variant confirmed in trans (PM3_Strong). At least one patient with this variant displayed VLCAD activity 20% of normal, which is highly specific for VLCAD deficiency (PP4; PMID: 9709714). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001759 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Recombinant protein expressing this variant showed reduced VLCAD enzyme activity, indicating that this variant impacts protein function (PS3_Supporting; PMID: 9461620). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Strong, PP4, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).