The c.1367G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 456 (p.Arg456His). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 30194637, 17206456). Of those individuals, one individual was presumed homozygous for the variant and two were confirmed compound heterozygous for the variant and a distinct variant, one of which is approved by the ACADVL VCEP as pathogenic (PM3, 1.5 points, PMIDs: 30194637, 17206456). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001709 in the 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). 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).