ClinVar Genomic variation as it relates to human health

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; 2 were heterozygous for the variant without an identified second distinct variant in ACADVL (PMIDs: 9973285, Olpin SE et al. Int J Neonat Screen. 2017 3(1),2); 3 individuals were homozygous for the variant (PM3 points = 1.0 max, PMID: 9973285) (PM3). 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 (PMID: 17374501) (PS3_Supporting). 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 (PMID: 9973285) (PM1). 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: PP4_Moderate, PM3, PM1, PS3_Supporting PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-13-2022).

The ACADVL c.1405C>T; p.Arg469Trp variant (rs113994170), also known as Arg429Trp, has been reported in multiple individuals with VLCAD deficiency, including three severely affected individuals that were homozygous for the variant (Andresen 1999). Additionally, functional studies have shown that the variant protein has significantly reduced enzymatic activity (Goetzman 2007, Hoffmann 2012). This variant is reported in ClinVar (Variation ID: 21017), and observed in the general population with low overall allele frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.003 percent (7/246250 alleles, Genome Aggregation Database). The arginine at codon 469 is well conserved across species, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77.

The NM_000018.3:c.1405C>T (NP_000009.1:p.Arg469Trp) [GRCH38: NC_000017.11:g.7224040C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the ACADVL protein (p.Arg469Trp). This variant is present in population databases (rs113994170, gnomAD 0.01%). This missense change has been observed in individual(s) with very–long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 17999356, 27246109). This variant is also known as R429W. ClinVar contains an entry for this variant (Variation ID: 21017). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. Experimental studies have shown that this missense change affects ACADVL function (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic.