ClinVar Genomic variation as it relates to human health

The c.385GAG[1] variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu130del) (PM4). This variant has been detected in at least five individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PMIDs 8554073, 10431122, 27209629,22847164). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those was confirmed in trans by parental testing (PM3_strong, PMID: 10431122). Several patients with this variant displayed VLCADD (PP4, PMIDs 8554073 , 10431122, 27209629, 22847164 ). Assays, including mRNA/protein expression (in CHO cells), and enzymatic activity demonstrate unstable protein products indicating that this variant impacts protein function (PMID: 8554073 )(PS3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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: PM4, PM3_strong, PP4, PS3

The ACADVL c.388_390delGAG; p.Glu130del variant (rs387906251) is reported in the literature in the compound heterozygous state in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (Hahn 1999, Pena 2016, Siu 2012, Souri 1996). In vitro functional analyses demonstrate production of unstable transcripts and reduced enzyme activity (Souri 1996). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 1626), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamic acid residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be pathogenic. References: Hahn SH et al. Very long chain acyl coenzyme A dehydrogenase deficiency in a 5-month-old Korean boy: identification of a novel mutation. J Pediatr. 1999 Aug;135(2 Pt 1):250-3. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Siu WK et al. Molecular diagnosis for a fatal case of very long-chain acyl-CoA dehydrogenase deficiency in Hong Kong Chinese with a novel mutation: a preventable death by newborn screening. Diagn Mol Pathol. 2012 Sep;21(3):184-7. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106.

Variant summary: ACADVL c.388_390delGAG (p.Glu130del) results in an in-frame deletion that is predicted to remove one of two glutamate residues in codon 388-390. The variant allele was found at a frequency of 2e-05 in 251410 control chromosomes (gnomAD). The variant, c.388_390delGAG, has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Souri_1996, Hahn_1999, Siu_2012, Miller_2015, Pena_2016). These data indicate that the variant is very likely to be associated with disease. One paper reports this variant retain less than 10% of enzyme activity compared to WT (Souri_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The ACADVL c.388_390delGAG variant is predicted to result in an in-frame deletion (p.Glu130del). This variant was reported in the homozygous and compound heterozygous state in multiple patients with biochemically confirmed very long chain acyl-CoA dehydrogenase deficiency (examples in Souri et al. 1996. PubMed ID: 8554073; Pena et al. 2016. PubMed ID: 27209629). In vitro functional characterization suggested that this variant is deleterious (Souri et al. 1996. PubMed ID: 8554073). This variant has been classified as pathogenic by the ClinGen ACADVL Variant Curation Expert Panel and the majority of clinvar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/1626/). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7124283-TGGA-T). This variant is interpreted as pathogenic.

The NM_000018.3:c.388_390delGAG (NP_000009.1:p.Glu130del) [GRCH38: NC_000017.11:g.7220969_7220971delGAG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8554073; 10431122. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750138126, gnomAD 0.01%). This variant has been observed in individual(s) with very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) Deficiency (PMID: 8554073, 10431122, 22847164, 27209629). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1626). Studies have shown that this variant alters ACADVL gene expression (PMID: 8554073). For these reasons, this variant has been classified as Pathogenic.

Functional studies found that the c.388_390del variant is associated with significantly reduced levels of VLCAD protein and reduced enzyme activity (PMID: 8554073); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22847164, 8554073, 30194637, 27209629, 33150772, 10431122)