The c.1405C>T variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 469 (p.Arg469Trp). This variant has been detected in at least 5 individuals with clinical signs of very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of these, 2 were heterozygous for the variant without an identified second variant in ACADVL (PMID: 9973285, Olpin SE et al. Int J Neonat Screen. 2017 3(1),2) and 3 individuals were homozygous for the variant (PM3 points = 1.0, PM3, PMID: 9973285). ACADVL activity in one patient's fibroblast cell line was observed at <=20% of normal (PMID: 17999356; PP4_Moderate). Expression of this variant using rACADVL in E. coli showed enzyme activity =< 20% of normal and absence of protein expression indicating that this variant impacts protein function; however, this assay did not use established benign variants as negative controls, and thus only meets criteria to be applied at supporting strength (PS3_Supporting; PMID: 17374501). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PM1; PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 in the EAS population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS3_Supporting, PM1, PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).