ClinVar

Description

Variant summary: ACADVL c.1844G>A (p.Arg615Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251176 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. An additional 5 homozygous occurrences have been reported in the literature in individuals with lack of phenotype (Abouelhoda_2016, Kars_2021). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) phenotype (0.0029), suggesting that the variant is a benign polymorphism. c.1844G>A has been reported in the literature as a biallelic genotype in individuals with mild forms of VLCAD deficiency and in individuals identified through Newborn Screening who were asymptomatic (e.g. Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016, Pena_2016). Residual enzymatic activities in compound heterozygous individuals carrying pathogenic variants in trans ranged from 21%, to 40% and up to similar activity to controls (Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016). In one simple heterozygous individual with the variant, residual enzymatic activity was measured at 39% (Hoffmann_2012), with the authors concluding from their study that individuals with a residual enzyme activity >20% present with a biochemical phenotype but likely remain asymptomatic throughout life. The variant was found to co-occur in cis with a pathogenic variant in one homozygous and one compound heterozygous individuals who had symptoms of VLCAD (Merinero_2018). Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, and four as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.