ACADVL p.Arg613Trp

The c.1837C>T variant in ACADVL is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 613 (p.Arg613Trp). This variant has been reported in ACADVL deficiency in numerous studies, including PMIDs:7479827, 8554073, 35281659, 17374501, 30194637. This variant is associated with increased C14:1 acylcarnitine levels in patients with ACADVL deficiency (PMID: 33986768, PP4_moderate). This variant was also detected in compound heterozygote with pathogenic variants from multiple patients (PM3, PMID: 7479827, 8554073, 30194637). This variant causes significantly reduced enzyme activity determined from lymphocytes, mammalian, and bacterial cell expression systems (PMID: 30194637, 8554073, 17374501, 33986768) and results in unstable protein product (PMID:8554073, PS3_supporting). This variant is also part of a C-terminal domain critical for mitochondiral membrane binding (PMID: 18227065). The highest population minor allele frequency in gnomAD is 0.0001 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary the ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PS3_supporting+PM3+PP3+PP4_moderate+PM2_supporting.