ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del) (rs387906251)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001693 SCV000220634 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-08-25 criteria provided, single submitter literature only
Invitae RCV000001693 SCV000773898 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-09-03 criteria provided, single submitter clinical testing This variant, c.388_390delGAG, 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, ExAC 0.03%). This variant has been observed as homozygous or as compound heterozygous (in trans) from other pathogenic ACADVL variants in several individuals affected with very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) Deficiency (PMID: 8554073, 10431122, 22847164, 27209629). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1626). Experimental studies have shown that this change leads to a reduced protein expression in vitro (PMID: 8554073). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000001693 SCV001160512 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-04-19 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001693 SCV001362322 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-04-26 criteria provided, single submitter clinical testing 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000001693 SCV001364888 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing 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
OMIM RCV000001693 SCV000021849 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1996-01-01 no assertion criteria provided literature only

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