ClinVar Genomic variation as it relates to human health

The ACADVL c.1591C>T (p.Arg531Trp) variant is a missense variant that has been reported in a compound heterozygous state with a canonical splice site variant in one individual with VLCAD deficiency who had residual enzyme activity of 21% (Hoffman et al. 2017). It has also been identified in a heterozygous state in four individuals with suspected VLCAD deficiency in whom a second variant was not identified (Miller et al. 2015; Ghosh et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000806 in the European (non-Finnish) population of the the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg531Trp variant is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The NM_000018.3:c.1591C>T (NP_000009.1:p.Arg531Trp) [GRCH38: NC_000017.11:g.7224379C>T] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM3, PP3, PP4

The c.1591C>T (p.R531W) alteration is located in exon 16 (coding exon 16) of the ACADVL gene. This alteration results from a C to T substitution at nucleotide position 1591, causing the arginine (R) at amino acid position 531 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.044% (123/281458) total alleles studied. The highest observed frequency was 0.076% (98/128338) of European (non-Finnish) alleles. This variant has been detected in conjunction with multiple ACADVL variants in individuals with clinical and biochemical features of VLCAD deficiency (Hoffmann, 2012; Rovelli, 2019; Olsson, 2022). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.

NM_000018.3(ACADVL):c.1591C>T(R531W) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. R531W has been observed in cases with relevant disease (PMID: 31031081, 28468868). Functional assessments of this variant are not available in the literature. R531W has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1591C>T(R531W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

The ACADVL c.1591C>T; p.Arg531Trp variant (rs146379816), also reported as p.Arg491Trp, is reported in the literature in the heterozygous state or in one case with a second variant presumed to be on the opposite chromosome in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (Adhikari 2020, Ghosh 2017, Hoffmann 2012, Rovelli 2019). This variant is also reported in ClinVar (Variation ID: 166647), and is found in the non-Finnish European population with an allele frequency of 0.076% (98/128338 alleles) in the Genome Aggregation Database. The arginine at codon 531 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.522). Due the limited amount of clinical and functional data, the significance of the p.Arg531Trp variant is uncertain at this time. References: Adhikari A et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020 Sep;26(9):1392-1397. PMID: 32778825. Ghosh A et al. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. Arch Dis Child. 2017 Nov;102(11):1019-1029. PMID: 28468868. 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. PMID: 21932095. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 531 of the ACADVL protein (p.Arg531Trp). This variant is present in population databases (rs146379816, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 31031081; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg491Trp. ClinVar contains an entry for this variant (Variation ID: 166647). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg531 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 27209629), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Variant summary: ACADVL c.1591C>T (p.Arg531Trp) results in a non-conservative amino acid change located in the ACAD9/ACADV-like, C-terminal domain (IPR049448) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 250116 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00044 vs 0.0029), allowing no conclusion about variant significance. c.1591C>T has been reported in the literature as a biallelic genotype in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Hoffmann_2012, Rovelli_2019, Olsson_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21932095, 28468868, 26385305, 31031081, 35281659, 34437764). ClinVar contains an entry for this variant (Variation ID: 166647). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.