ACADVL p.Ser423=

The c.1269G>A (NM_000018.4) variant in ACADVL is a synonymous variant which occurs in the final nucleotide of exon 12, a position that is generally considered highly conserved. At least one patient with this variant displayed reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels in lymphocytes, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 30194637). The highest population minor allele frequency in gnomAD v4.1.1 0.00001335 in African/African American 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 splicing predictor SpliceAI gives a score of 0.79 for donor loss, predicting that the variant disrupts the donor splice site of intron 12 of ACADVL (PP3). This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency in a potential compound heterozygous state with a likely pathogenic variant, but this information is insufficient to use toward classification (PMID: 30194637). It has also been detected in one patient that was compound heterozygous for the variant and likely pathogenic variant (c.1055T>C (p.Met352Thr)) confirmed in trans by parental testing (PMID: 40678976), but this information is insufficient to use toward classification as no biochemical data for this patient is available (PM3 not applied). RT-PCR, ACADVL Minigene, Plasmid Construction and ACADVL expression analysis in 293T and HeLa cells showed skip of exon 12 and decreased mRNA expression indicating that this variant impacts protein function (PMID: 40678976) PVS1_RNA). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_RNA,PM2_supporting, PP4_Moderate (ACADVL VCEP specifications version 2.1.0; approved September 4, 2025).